Novel benzimidazole derivative having jnk inhibitory activity and use thereof

ABSTRACT

The present invention relates to a novel benzimidazole derivative having JNK (C-Jun N-terminal kinase) inhibitory activity and use thereof. The novel benzimidazole derivative or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent inhibitory activity against c-Jun N-terminal kinase 3(JNK 3), and thus it is expected that target therapy can be attained through a more fundamental approach in the prevention or treatment of degenerative brain-nerve system disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/KR2018/001999 filed Feb. 19, 2018, which claims benefit of priorityto Korean Patent Application No. 10-2017-0022188 filed Feb. 20, 2017.The entire contents of the above applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a novel benzimidazole derivative havingC-Jun N-terminal kinase (JNK) inhibitory activity and a use thereof.

BACKGROUND ART

Recently, the number of patients suffering from neurodegenerative braindiseases is rapidly increasing with an increase in the elderlypopulation. Neurodegenerative brain diseases may be caused by adultdisease-derived secondary symptoms such as aging-induced structuraldegeneration of neurons, circulatory disorders, and the like, orphysical and mechanical factors such as traffic accidents, industrialaccidents, carbon monoxide poisoning, and the like, and as relateddiseases, Alzheimer' disease, Parkinson' disease, Huntington's disease,multiple sclerosis, stroke, and the like are known.

Meanwhile, c-Jun N-terminal kinase (JNK), which is classified as aserine/threonine kinase, is one of the three subfamilies ofmitogen-activated protein kinases and is also referred to as stressactivated protein kinase (SAPK). It is known that JNK is activated inresponse to a variety of stimuli such as cytokines, mitogens, osmoticstress, ultraviolet irradiation, and the like, and the activated JNKpromotes the phosphorylation of a variety of transcription factorsincluding c-Jun of AP-1 and intracellular proteins related to apoptosis,such as Bcl2, p53, and the like. In addition, JNK genes form differenttypes of isoforms by splicing. Among them, the distribution of JNK3 isconcentrated in brain tissue unlike the same kind of isoforms, thenumber of which is about 10, and thus various studies have beenconducted on the relationship between JNK3 and neurodegenerative braindisease.

In particular, it has been reported that JNK3 phosphorylates andactivates amyloid precursor protein (APP), which is the main cause ofAlzheimer's disease, to thus allow the APP to be located in a cellmembrane, promotes the conversion of APP to beta-amyloid, and in a casein which, after beta-amyloid is formed, the apoptosis of neurons isinduced by toxicity thereof, the activation of JNK3 acts as a maincause. In addition, a dramatic decrease in oligomeric beta-amyloid andan increase in cognitive ability, caused by the removal of JNK3, areobserved in mice with familial Alzheimer's disease (FAD), and resistanceto MPTP, which is a Parkinson's disease-inducing material, is acquiredin mice from which the JNK3 gene is removed, and an effect of inhibitingside effects of glutamate analogs, which are neurotoxic substances, hasbeen found in the mice.

Under these circumstances, research on the discovery of a JNK3 inhibitoras a novel substance for the treatment of neurodegenerative braindiseases has been actively conducted (Korean Patent Publication No.2001-0029352), and it is still not adequate.

Technical Problem

The present invention has been made to address the above-describedproblems, and as a result of having conducted intensive research todiscover a novel material having the possibility of being developed as atherapeutic agent for neurodegenerative brain diseases, the inventors ofthe present invention identified a novel benzimidazole derivative havingJNK inhibitory activity, and thus completed the present invention basedon these findings.

Therefore, an object of the present invention is to provide a novelbenzimidazole derivative having JNK inhibitory activity or apharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a novelbenzimidazole derivative having JNK inhibitory activity.

Another object of the present invention is to provide a pharmaceuticalcomposition for preventing or treating a neurodegenerative braindisease, which includes, as an active ingredient, the benzimidazolederivative or a pharmaceutically acceptable salt thereof.

However, technical problems to be solved by the present invention arenot limited to the above-described technical problems, and otherunmentioned technical problems will become apparent from the followingdescription to those of ordinary skill in the art.

Technical Solution

To achieve the above objectives of the present invention, there isprovided a benzimidazole derivative represented by Formula 1 below or apharmaceutically acceptable salt thereof.

wherein, in Formula 1, R₁ is selected from the group consisting ofbenzooxazolyl, benzodioxazolyl, 1,3-benzodioxolyl, 1,4-benzodioxinyl,dihydrobenzodioxinyl, benzothiazolyl, benzothiophenyl, quinolinyl,isoquinolinyl, indolyl, benzofuranyl, purinyl, and indolizinyl;

R₂ and R₃ are each independently hydrogen or hydroxy;

R₄ represents a C₃-C₁₀ cycloalkyl or a C₄-C₁₀ heterocycloalkyl whereinthe C₄-C₁₀ heterocycloalkyl is selected from the group consisting oftetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, and piperidinyl; and

R₄ may be substituted or unsubstituted with a C₄-C₁₀ cycloalkylcarbonyl.

The present invention also provides a pharmaceutical composition forpreventing or treating a neurodegenerative brain disease, whichincludes, as an active ingredient, the derivative of Formula 1 or apharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the neurodegenerative braindisease may be selected from the group consisting of Alzheimer' disease,Parkinson' disease, Huntington's disease, multiple sclerosis, andstroke.

In another embodiment of the present invention, the composition mayinhibit the activity of C-Jun N-terminal kinase 3 (JNK 3).

The present invention also provides a method of treating aneurodegenerative brain disease, including administering, to anindividual, the derivative of Formula 1 or a pharmaceutically acceptablesalt thereof.

The present invention also provides a use of the derivative of Formula 1or a pharmaceutically acceptable salt thereof for the treatment of aneurodegenerative brain disease.

Advantageous Effects of Invention

A novel benzimidazole derivative or a pharmaceutically acceptable saltthereof according to the present invention exhibits excellent inhibitoryactivity against c-Jun N-terminal kinase 3 (JNK 3), and thus apharmaceutical composition including the derivative is expected to beeffectively used for the prevention and treatment of neurodegenerativebrain diseases.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates western blotting results of confirming changes in theconcentration of APP and beta-amyloid oligomer in the frontal lobecortex according to treatment with a derivative of the presentinvention.

FIG. 2 is a schematic view illustrating a migration evaluation system ofthe blood-brain barrier (BBB).

DETAILED DESCRIPTION

Hereinafter, the present invention will be described in detail.

To achieve the above objectives of the present invention, there isprovided a benzimidazole derivative represented by Formula 1 below or apharmaceutically acceptable salt thereof.

wherein, in Formula 1, R₁ is selected from the group consisting ofbenzooxazolyl, benzodioxazolyl, 1,3-benzodioxolyl, 1,4-benzodioxinyl,dihydrobenzodioxinyl, benzothiazolyl, benzothiophenyl, quinolinyl,isoquinolinyl, indolyl, benzofuranyl, purinyl, and indolizinyl; R₂ andR₃ are each independently hydrogen or hydroxy; R₄ represents a C₃-C₁₀cycloalkyl or a C₄-C₁₀ heterocycloalkyl wherein the C₄-C₁₀heterocycloalkyl is selected from the group consisting oftetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, and piperidinyl; and R₄ may besubstituted or unsubstituted with a C₄-C₁₀ cycloalkylcarbonyl.

As used herein, the “substituted” group indicates that one or morehydrogen atoms of the corresponding group is substituted with one ormore non-hydrogen atoms, wherein valence requirements must be satisfiedand a chemically stable compound must be generated from substitution.Unless the term “unsubstituted” is stated explicitly in the presentspecification, all substituents should be construed as being able to besubstituted or unsubstituted. The substituent of R₄ of the benzimidazolederivative according to the present invention may be substituted againwith one or more selected from the substituents defined above.

The term “cycloalkyl” refers to a saturated monocyclic or polycyclichydrocarbon ring which generally contains a ring and has the indicatednumber of carbon atoms (i.e., a C₃₋₁₀ cycloalkyl refers to a cyclic ringhaving 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms as ring members). Theterm “heterocycloalkyl” refers to a monocyclic or polycyclic heterocyclegroup containing 1 to 4 heteroatoms each independently selected fromnitrogen, oxygen, and sulfur, and non-limiting examples of theheterocycloalkyl include tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, anddihydrobenzodioxinyl. A cycloalkyl and a heterocycloalkyl may be linkedto a parent group or a substrate in an arbitrary ring atom as long asthe linkage satisfies valence requirements. Similarly, a cycloalkyl anda heterocycloalkyl may include one or more non-hydrogen substituents aslong as the linkage satisfies valence requirements.

The term “carbonyl” refers to —C(O)R′. As used herein, (0) refers to astate in which oxygen is bound via a double bond to an atom such ascarbon or sulfur. In this regard, R′ refers to a non-hydrogensubstituent such as a lower alkyl, a lower alkoxy, or the like.Non-limiting examples of the carbonyl group include 2-methoxyoxoethyland 3-methoxyoxopropyl. A carbonyl may be linked to a parent group or asubstrate in an arbitrary ring atom as long as the linkage satisfiesvalence requirements. Similarly, a carbonyl group may include one ormore non-hydrogen substituent as long as the linkage satisfies valencerequirements.

In addition, the benzimidazole derivative of Formula 1 may include acompound in the form of a racemate or isomer thereof.

In the benzimidazole derivative of Formula 1 of the present invention,R₁ represents 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,quinolinyl, or benzofuranyl;

R₂ and R₃ are each independently hydrogen or hydroxy; R₄ is cyclohexyl,tetrahydropyranyl, or piperidinyl; and R₄ may be substituted orunsubstituted with a C₄-C₁₀ cycloalkylcarbonyl.

In another embodiment of the present invention, R₁ represents1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, quinolinyl, orbenzofuranyl; R₂ and R₃ are each independently hydrogen or hydroxyl; andR₄ may be cyclohexyl, tetrahydropyranyl, or cyclopropyl methanonepiperidinyl.

In another embodiment of the present invention, the benzimidazolederivative of Formula 1 may be2-(quinoline-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol;2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol;2-(benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol;1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazole-5-ol;2-(benzofuran-5-yl)-1-(2-(cyclohexylamine)pyrimidien-4-yl)-1H-benzo[d]imidazole-5-ol;(S)-cyclopropyl(3-((4-(5-hydroxy-2-(quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone;(S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone;(S)-(3-(4-(2-(benzofuran-5-yl)-5-hydroxy-1H-benz[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone;(S)-(3-(4-(2-(benzo[d][1,3]dioxol-5-yl)-5-hydroxy-1H-benz[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone;2-(quinoline-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol;2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-ylamino)pyriidine-4-yl)-1H-benzo[d]imidazole-6-ol;2-(benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol;3-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(quinoline-2-yl)-3H-benz[d]imidazole-5-ol;1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazole-6-ol;2-(benzofuran-5-yl)-1-(2-(cyclohexylamino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol;(S)-cyclopropyl(3-(4-(6-hydroxy-2-(quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone;(S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone;(S)-(3-((4-(2-(benzofuran-5-yl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)(cyclopropyl)methanone;(R)-cyclopropyl(3-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dihydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone;or(R)-(3-(4-(2-(benzofuran-5-yl)-5,6-dihydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone.

In particular, the benzimidazole derivative of Formula 1 may exhibit, aseffects due to hetero-substituents introduced into the R₁ group, notonly higher BBB permeability than that of conventional derivatives, butalso enhanced liposolubility for the preparation of a drug according tothe introduction of a hydroxy group, and thus may be expected to exhibita stronger brain disease treatment effect.

Meanwhile, the compound of the present invention may be used in the formof a pharmaceutically acceptable salt, and as the salt, an acid additionsalt formed by a pharmaceutically acceptable free acid is useful.

The term “salt” as used herein refers to an acid addition salt formed bya pharmaceutically acceptable free acid. The acid addition salt isobtained from: inorganic acids such as hydrochloric acid, nitric acid,phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid,nitrous acid, and phosphorous acid; or nontoxic organic acids such asaliphatic mono- and dicarboxylates, phenyl-substituted alkanoates,hydroxy alkanoates and alkandioates, aromatic acids, and aliphatic andaromatic sulfonic acids. Examples of these pharmaceutically nontoxicsalts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates,metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides,acetates, propionates, decanoates, caprylates, acrylates, formates,isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates,succinates, suberates, sebacates, fumarates, maleates,butyne-1,4-dioates, hexane-1,6-dioates, benzoates, chlorobenzoates,methylbenzoates, dinitro benzoates, hydroxybenzoates, methoxybenzoates,phthalates, terephthalates, benzenesulfonates, toluenesulfonates,chlorobenzene sulfonates, xylenesulfonates, phenylacetates,phenylpropionates, phenylbutyrates, citrates, lactates,P-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates,propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,and mandelates.

Acid addition salts according to the present invention may be preparedusing a conventional method, for example, by dissolving the compounds ofFormula 1 in an excess aqueous acid solution and precipitating the saltusing a water-miscible organic solvent, e.g., methanol, ethanol,acetone, or acetonitrile. The acid addition salts may also be preparedby evaporating and drying the solvent or an excess acid in the resultingmixture or suction-filtering the precipitated salt.

In addition, pharmaceutically acceptable metallic salts may be preparedusing bases. Alkali metal or alkaline earth metal salts are obtained by,for example, dissolving a compound in an excess alkali metal hydroxideor alkaline earth metal hydroxide solution, filtering a non-solublecompound salt, and evaporating and drying the filtrate. At this time, itis pharmaceutically preferable that a sodium salt, a potassium salt, ora calcium salt is prepared as a metal salt. In addition, silver saltscorresponding thereto are obtained by reacting an alkali metal or analkaline earth metal salt with a suitable silver salt (e.g., silvernitrate).

Moreover, the compound of the present invention includes not onlypharmaceutically acceptable salts thereof, but also all salts, isomers,hydrates, and solvates that may be prepared using general methods.

Meanwhile, the benzimidazole derivative of Formula 1 according to thepresent invention may be prepared using several methods.

In one embodiment, as shown in Reaction Scheme 1 below, 60% NaH and aDMF solution were added to Compound 1a, Compound 14a, followed bystirring, a hydrogenation reaction, benzoimidazole formation usingsubstituents (R₁), and an oxidation reaction using oxone to therebysynthesize Compounds 15a-g, Compounds 18a-g, and then each compound issubjected to a series of aromatic nucleophilic substitution reactions,thereby completing the synthesis of Compounds 9a-g, Compounds 10a-g, andCompounds 11a-g or Compounds 22a-g, Compounds 23a-g, and Compounds25a-g, which are benzimidazole derivatives of the present invention.

Reagents and reaction condition (i) 60% NaH, DMF, 0° C. to rt, 2 h; (ii)Pd/C, H₂, MeOH, rt, 6 h; (iii) Ar, Na₂S₂O₅, DMF, Microwave (120° C., 150W, 30 min); (iv) oxone, MeOH:H₂O=1:1, rt, 1 h; (v) NH₂R, THF, 60° C., 5h; (vi) 4N—HCl in 1,4-dioxane, rt, 20 min; (vii) cyclopropanecarbonylchloride, TEA, THF, 0° C. to rt, 1 h; (ix) BBr₃, DCM, −78° C. to rt, 2 h

In another embodiment, as shown in Reaction Scheme 2 below, Compounds35a-g, which are benzimidazole derivatives of the present invention,were synthesized.

In addition, in an experimental example of the present invention, it wasobserved that the benzimidazole derivatives prepared in accordance withthe synthesis mechanisms of Reaction Schemes 1 and 2 exhibited excellentJNK3 inhibitory activity and a consequent effect of reducing theconcentration of beta-amyloid oligomer in brain tissue, and effectivelypermeated the blood-brain barrier compared to other drugs. Thus, throughthese experimental results, it was confirmed that the derivatives of thepresent invention could be effectively used as an active ingredient forthe treatment of neurodegenerative brain diseases (see ExperimentalExamples 1 to 3).

Therefore, the present invention provides a pharmaceutical compositionfor the prevention or treatment of a neurodegenerative brain disease,which includes, as an active ingredient, the benzimidazole derivative ofFormula 1 or a pharmaceutically acceptable salt thereof, a use of thebenzimidazole derivative of Formula 1 or a pharmaceutically acceptablesalt thereof for treating the above disease, and a method of treatingthe above disease, including administering, to an individual, atherapeutically effective amount of the compound of Formula 1 or apharmaceutically acceptable salt thereof.

The term “prevention” as used herein means all actions that inhibitneurodegenerative brain diseases or delay the onset thereof viaadministration of the pharmaceutical composition according to thepresent invention.

The term “treatment” as used herein means all actions that alleviate orbeneficially change symptoms due to neurodegenerative brain diseases viaadministration of the pharmaceutical composition according to thepresent invention.

The term “neurodegenerative brain disease”, which is a disease to beprevented or treated by the composition of the present invention, mayinclude diseases occurring due to brain damage without limitation, butpreferably, the disease may be Alzheimer' disease, Parkinson' disease,Huntington's disease, multiple sclerosis, or stroke.

The pharmaceutical composition of the present invention includes apharmaceutically acceptable carrier, in addition to the activeingredient. At this time, the pharmaceutically acceptable carrier, whichis commonly used in formulation, may be lactose, dextrose, sucrose,sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates,gelatin, calcium silicate, micro-crystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose,methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesiumstearate, and mineral oil, but the present invention is not limitedthereto. In addition, the pharmaceutical composition may furtherinclude, in addition to the above-described components, a lubricant, awetting agent, a sweetener, a flavor enhancer, an emulsifying agent, asuspension agent, a preservative, or the like.

The pharmaceutical composition of the present invention may beadministered orally or parenterally (for example, intravenousadministration, subcutaneous administration, intraperitonealadministration, or topical administration) according to a desiredmethod, and a dose thereof may vary depending on the condition and bodyweight of a patient, the severity of diseases, drug form, administrationroute, and administration time, but may be appropriately selected bythose of ordinary skill in the art.

The pharmaceutical composition of the present invention is administeredin a pharmaceutically effective amount. The term “pharmaceuticallyeffective amount” as used herein refers to an amount sufficient to treatdiseases at a reasonable benefit/risk ratio applicable to medicaltreatment, and an effective dosage level may be determined according tofactors including type of diseases of patients, the severity of disease,the activity of drugs, sensitivity to drugs, administration time,administration route, excretion rate, treatment period, andsimultaneously used drugs, and other factors well known in the medicalfield. The pharmaceutical composition according to the present inventionmay be administered as an individual therapeutic agent or in combinationwith other therapeutic agents, sequentially or simultaneously withconventional therapeutic agents, and may be administered in a singledose or multiple doses. It is important to administer the pharmaceuticalcomposition in the minimum amount that enables achievement of themaximum effects without side effects in consideration of all theabove-described factors, and this may be easily determined by those ofordinary skill in the art.

In particular, an effective amount of the pharmaceutical composition ofthe present invention may vary according to the age, gender, condition,and body weight of a patient, the absorption, inactivity, and excretionrate of active ingredients in the body, the type of disease, andsimultaneously used drugs, and the pharmaceutical composition maygenerally be administered in an amount of 0.001 mg/lkg (body weight) to150 mg/kg, preferably 0.01 mg/kg to 100 mg/kg daily or every second day,or may be administered one to three times per day. However, the dosagemay be increased or decreased according to administration route, theseverity of obesity, gender, body weight, age, and the like, and thusthe dosage is not intended to limit the scope of the present inventionin any way.

The term “individual” as used herein refers to a subject with a diseaserequiring treatment and, more particularly, includes mammals such ashumans, non-human primates, mice, rats, dogs, cats, horses, cows, andthe like.

I. Synthesis of Benzimidazol-5-ol Derivatives <Preparation Example 1-1>N-(4-methoxy-2-nitrophenyl)-2-(methylthio)pyrimidine-4-amine (2)

4-methoxy 2-nitrobenzene amine (Compound 1; 3 g, 17.85 mmol) wasdissolved in DMF (89 ml), and 60% NaH (893 mg) was slowly added theretoat 0° C. Subsequently, the resulting solution was stirred for about 1hour, 4-chloro-2-(methylthio)pyrimidine (5.73 g, 17.85 mmol) was addedthereto, followed by stirring for about 2 hours. Thereafter, the mixedsolvent was poured into iced water to be precipitated, and theprecipitated reaction product was filtered to thereby obtain compound 2(4 g, 78%).

¹H NMR (400 MHz, CDCl₃) δ 9.78 (s, 1H), 8.58 (d, J=9.3 Hz, 1H), 8.19 (d,J=5.8 Hz, 1H), 7.65 (d, J=3.0 Hz, 1H), 7.24 (dd, J=9.3, 3.0 Hz, 1H),6.47 (d, J=5.8 Hz, 1H), 3.86 (s, 3H), 2.52 (s, 3H).

<Preparation Example1-2>4-methoxy-N-(2-(methylthio)pyrimidin-4-yl)benzene-1,2-diamine (3)

Compound 2 (1433 mg, 4.9 mmol) was dissolved in methanol (33 ml), 10%Pd/C (143 mg) was added thereto, and the resulting solution was stirredin the presence of hydrogen gas at room temperature for 5 hours. Afterthe reaction was completed, the reaction product was filtered withCelite and the filtrate was distilled under reduced pressure. Compound 3(1280 mg, 99%) was obtained from the residue without any purification.

¹H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 7.95 (d, J=5.9 Hz, 1H), 6.93 (d,J=5.9 Hz, 1H), 6.33 (d, J=2.8 Hz, 1H), 6.15 (dd, J=8.6, 2.8 Hz, 1H),5.98 (s, 1H), 4.94 (s, 2H), 3.67 (s, 3H), 2.39 (s, 3H).

<Preparation Example1-3>5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazole(4a)

Compound 3 (400 mg, 1.52 mmol), 2-naphthaldehyde (260 mg, 1.67 mmol),and Na₂S₂O₅ (1.45 g) were dissolved in DMF (3 ml), and the resultingsolution was stirred in a microwave at 120° C. and 150 W for 1.5 hours.After confirming that the reaction was completed, the solvent was pouredinto iced water to be precipitated. The precipitated reaction productwas filtered, and the filtrate was distilled under reduced pressure, andthe residue was purified with column chromatography (silica gel,n-hexane:ethyl acetate=3:1), thereby obtaining compound 4a (370 mg,50%).

¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=5.4 Hz, 1H), 8.21 (d, J=1.3 Hz,1H), 7.88 (d, J=1.8 Hz, 1H), 7.86-7.84 (m, 2H), 7.83 (s, 1H), 7.59-7.49(m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.02 (dd, J=9.0, 2.5 Hz, 1H), 6.53 (d,J=5.4 Hz, 1H), 3.90 (s, 3H), 2.48 (s, 3H).

Compounds prepared according to Preparation Examples 1-4 to 1-9 wereobtained in the same manner as in Preparation Example 1-3 (Compound 4b(360 mg, 59%), Compound 4c (403 mg, 59%), Compound 4d (325 mg, 64%),Compound 4e (588 mg, 86%), Compound 4f (370 mg, 56%), and Compound 4g(210 mg, 34%)).

<Preparation Example1-4>2-(5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole-2-yl)quinolone(4b)

¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=5.3 Hz, 1H), 8.32 (d, J=8.5 Hz,1H), 8.23 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.60 (dd, J=4.6,2.0 Hz, 2H), 7.55 (d, J=9.0 Hz, 1H), 7.50 (m, 1H), 7.35 (d, J=2.4 Hz,1H), 7.00 (dd, J=9.0, 2.4 Hz, 1H), 6.83 (d, J=5.3 Hz, 1H), 3.86 (s, 3H),2.36 (s, 3H).

<Preparation Example1-5>2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(4c)

¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=5.4 Hz, 1H), 7.76 (d, J=8.9 Hz,1H), 7.30 (d, J=2.3 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 7.00-6.93 (m, 2H),6.86 (d, J=8.4 Hz, 1H), 6.56 (d, J=5.4 Hz, 1H), 4.28 (m, 2H), 4.27-4.23(m, 2H), 3.87 (s, 3H), 2.54 (s, 3H).

<Preparation Example1-6>2-(benzofuran-5-yl)-5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(4d)

¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=5.4 Hz, 1H), 7.77 (d, J=1.4 Hz,1H), 7.70 (d, J=8.9 Hz, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.43 (d, J=8.6 Hz,1H), 7.35 (dd, J=8.6, 1.7 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.88 (dd,J=8.9, 2.5 Hz, 1H), 6.70 (dd, J=2.2, 0.8 Hz, 1H), 6.37 (d, J=5.4 Hz,1H), 3.79 (s, 3H), 2.39 (s, 3H).

<Preparation Example1-7>2-(3,4-dichlorophenyl)-5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(4e)

¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=5.3 Hz, 1H), 7.74 (d, J=2.3 Hz,1H), 7.66 (d, J=9.0 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.27-7.20 (m, 2H),6.95 (dd, J=9.0, 2.3 Hz, 1H), 6.59 (d, J=5.3 Hz, 1H), 3.83 (s, 3H), 2.41(s, 3H).

<Preparation Example1-8>2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(4f)

¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=5.3 Hz, 1H), 7.94 (dd, J=6.5, 1.5Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.24 (d, J=2.2 Hz,1H), 7.17 (m, 1H), 6.93 (dd, J=9.0, 2.2 Hz, 1H), 6.67 (d, J=5.3 Hz, 1H),3.81 (s, 3H), 2.34 (s, 3H).

<Preparation Example1-9>2-(benzo[d][1,3]dioxole-5-yl)-5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(4g)

¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=5.4 Hz, 1H), 7.78 (d, J=8.9 Hz,1H), 7.30 (d, J=2.4 Hz, 1H), 7.04 (d, J=1.4 Hz, 1H), 7.02 (dd, J=8.0,1.7 Hz, 1H), 6.97 (dd, J=9.0, 2.5 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.56(d, J=5.4 Hz, 1H), 6.02 (s, 2H), 3.88 (s, 3H), 2.55 (s, 3H).

<Preparation Example1-10>5-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazole(5a)

Compound 4a (500 mg, 1.25 mg) and Potassium peroxomonosulfate (3.8 g)were dissolved in MeOH:H2O=1:1 mixed solvent (7 ml) and stirred at roomtemperature for 1 hour. After confirming the reaction, methanol wasdistilled off under reduced pressure. To the distilled mixture wasdiluted by addition of water and stirred until the product separated toa solid. The solid product was filtered off and washed with water andthen the crude product was crystallized to obtain Compound 5a (530 mg,98%).

¹H NMR (400 MHz, DMSO) δ 9.00 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 8.02 (d,J=8.9 Hz, 4H), 7.68-7.58 (m, 3H), 7.44 (d, J=5.6 Hz, 1H), 7.41 (t, J=3.5Hz, 1H), 7.10 (dd, J=9.1, 2.4 Hz, 1H), 3.87 (s, 3H), 3.31 (s, 3H).

In the same manner as in Preparation Example 1-10, the compounds ofPreparation Examples 1-12 to 1-16 were obtained. (Compound 5b (305 mg,99%), 5c (315 mg, 90%), 5d (356 mg, 89%), 5e (220 mg, 95%), 5f (348 mg,94%), 5g (200 mg, 87%)).

<Preparation Example1-11>2-(5-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole-2-yl)quinolone(5b)

¹H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 8.59 (d, J=7.7 Hz, 1H), 8.39 (d,J=7.5 Hz, 1H), 8.04 (d, J=6.9 Hz, 1H), 7.94 (s, 1H), 7.71 (m, 2H), 7.64(s, 1H), 7.45 (s, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H),3.86 (s, 3H), 3.35 (s, 3H).

<Preparation Example1-12>2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(5c)

¹H NMR (400 MHz, DMSO) δ 9.12 (d, J=5.5 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H),7.51 (d, J=5.5 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H),7.10 (dd, J=9.0, 2.4 Hz, 1H), 7.02 (dd, J=8.4, 2.0 Hz, 1H), 6.97 (d,J=8.4 Hz, 1H), 4.33 (d, J=4.7 Hz, 2H), 4.30 (d, J=4.7 Hz, 2H), 3.86 (s,3H), 3.41 (s, 3H).

<Preparation Example1-13>2-(benzofuran-5-yl)-5-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(5d)

¹H NMR (400 MHz, DMSO) δ 9.07 (d, J=5.5 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H),8.03 (d, J=1.7 Hz, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H),7.56 (dd, J=8.6, 1.7 Hz, 1H), 7.43 (m, 2H), 7.16 (dd, J=9.1, 2.4 Hz,1H), 7.09 (d, J=1.5 Hz, 1H), 3.88 (s, 3H), 3.36 (s, 3H).

<Preparation Example1-14>2-(3,4-dichlorophenyl)-5-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(5e)

¹H NMR (400 MHz, DMSO) δ 9.10 (d, J=5.5 Hz, 1H), 7.97-7.94 (m, 2H), 7.71(d, J=8.4 Hz, 1H), 7.60 (d, J=5.5 Hz, 1H), 7.52 (dd, J=8.4, 1.9 Hz, 1H),7.38 (d, J=2.3 Hz, 1H), 7.09 (dd, J=9.0, 2.3 Hz, 1H), 3.85 (s, 3H), 3.35(s, 3H).

<Preparation Example1-15>2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(5f)

¹H NMR (400 MHz, DMSO) δ 9.12 (d, J=5.5 Hz, 1H), 8.10 (d, J=5.9 Hz, 1H),7.96-7.88 (m, 2H), 7.66 (d, J=5.5 Hz, 1H), 7.61 (d, J=9.7 Hz, 1H), 7.39(d, J=2.1 Hz, 1H), 7.08 (dd, J=9.0, 2.1 Hz, 1H), 3.85 (s, 3H), 3.33 (s,3H).

<Preparation Example1-16>2-(benzo[d][1,3]dioxole-5-yl)-5-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(5g)

¹H NMR (400 MHz, DMSO) δ 9.11 (d, J=5.5 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H),7.49 (d, J=5.5 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 7.21 (d, J=1.5 Hz, 1H),7.13-7.08 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.15 (s, 2H), 3.86 (s, 3H),3.42 (s, 3H).

<Preparation Example1-17>4-(5-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(6a)

Compound 5a (43 mg, 0.1 mmol) and tetrahydro-2H-pyran-4-amine (21 ul)were dissolved in THF (1 ml) and stirred at 60° C. for 5 hours. Afterconfirming that the reaction was completed, the reaction mixture wascooled to ambient temperature and the filtrate was distilled underreduced pressure, and the residue was purified by column chromatography(silica gel, n-hexane:ethyl acetate=2:1) to obtain Compound 6a (31 mg,68%).

¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 8.23 (s, 1H), 7.927.76 (m, 3H),7.67 (s, 1H), 7.56-7.45 (m, 3H), 7.38 (d, J=1.9 Hz, 1H), 6.99 (dd,J=8.9, 2.4 Hz, 1H), 6.38 (d, J=160.1 Hz, 1H), 5.47 (s, 1H), 3.90 (s,3H), 3.50 (m, 2H), 3.39-3.21 (m, 1H), 2.93 (m, 1H), 1.58-1.30 (m, 2H),1.24 (m, 2H), 1.15-0.81 (m, 1H).

In the same manner as in Preparation Example 1-17, the compounds ofPreparation Examples 1-18 to 1-23 were obtained (Compound 6b (37 mg,81%), 6c (44 mg, 83%), 6d (36 mg, 66%), 6e (33 mg, 51%), 6f (39 mg,74%), 6g (27 mg, 55%)).

<Preparation Example1-18>4-(5-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidine-2-amine(6b)

¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=5.3 Hz, 1H), 8.27 (d, J=7.9 Hz,2H), 7.82 (d, J=7.9 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.65 (m, 1H),7.56-7.51 (m, 2H), 7.38 (d, J=2.3 Hz, 1H), 7.02 (dd, J=8.9, 2.3 Hz, 1H),6.63 (s, 1H), 3.89 (s, 3H), 3.76 (m, 2H), 3.44 (s, 1H), 3.32-2.91 (m,2H), 1.24 (m, 4H), 1.09-0.73 (m, 1H).

<Preparation Example1-19>4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(6c)

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=4.5 Hz, 1H), 7.59 (s, 1H), 7.31 (d,J=2.0 Hz, 1H), 7.13 (s, 1H), 7.04 (dd, J=8.4, 2.0 Hz, 1H), 6.92 (dd,J=8.9, 2.3 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.40 (s, 1H), 4.25 (dd,J=11.3, 4.9 Hz, 4H), 3.95 (s, 1H), 3.86 (s, 3H), 3.49-3.31 (m, 2H), 1.76(m, 2H), 1.50 (m, 3H), 1.30-1.18 (m, 1H), 1.01-0.78 (m, 1H).

<Preparation Example1-20>4-(2-(benzofuran-5-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(6d)

¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.91 (d, J=1.0 Hz, 1H), 7.67 (d,J=2.2 Hz, 1H), 7.66-7.55 (s, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 7.36 (d, J=2.2 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 6.80 (dd,J=2.1, 1.0 Hz, 1H), 6.45 (s, 1H), 3.88 (s, 3H), 3.76 (m, 1H), 3.52 (s,1H), 3.17 (m, 1H), 2.13-1.84 (m, 1H), 1.56 (m, 2H), 1.48-1.28 (m, 2H),1.27-1.20 (m, 1H), 1.03-0.74 (m, 1H).

<Preparation Example1-21>4-(2-(3,4-dichlorophenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(6e)

¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=3.8 Hz, 1H), 7.79 (s, 1H), 7.57 (s,1H), 7.45 (d, J=8.3 Hz, 1H), 7.32 (m, 2H), 6.99 (dd, J=8.9, 2.0 Hz, 1H),6.58 (s, 1H), 3.93 (s, 1H), 3.88 (s, 3H), 3.61-3.16 (m, 3H), 1.83-1.35(m, 4H), 1.24 (m, 1H), 1.19-0.74 (m, 1H).

<Preparation Example1-22>4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(6f)

¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 7.95 (d, J=6.3 Hz, 1H), 7.71 (s,1H), 7.57 (d, J=6.9 Hz, 1H), 7.33 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.00(d, J=8.0 Hz, 1H), 6.56 (s, 1H), 3.88 (s, 3H), 3.52 (s, 1H), 3.45-3.21(m, 2H), 2.24-1.82 (m, 1H), 1.61 (m, 2H), 1.55-1.39 (m, 2H), 1.33-1.17(m, 1H), 0.98 (m, 1H).

<Preparation Example1-23>4-(2-(benzo[d][1,3]dioxole-5-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(6g)

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.1 Hz, 1H), 7.62 (s, 1H), 7.30 (d,J=1.8 Hz, 1H), 7.12-7.02 (m, 2H), 6.94 (dd, J=8.9, 2.4 Hz, 1H), 6.82 (d,J=8.3 Hz, 1H), 6.39 (s, 1H), 6.00 (s, 2H), 3.94 (m, 2H), 3.83-3.61 (br,1H), 3.58-3.33 (m, 2H), 1.95-1.67 (m, 2H), 1.66-1.48 (m, 2H), 1.02-0.81(m, 1H).

<Preparation Example 1-24>N-cyclohexyl-4-(5-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(7a)

Compound 5a (46 mg, 0.11 mmol) and cyclohexanamine (25 μl) weredissolved in THF (1.1 ml) and stirred at 60° C. for 5 hours. Aftercompletion of the reaction, the reaction mixture was cooled to ambienttemperature and the filtrate was distilled under reduced pressure, andthe residue was purified by column chromatography (silica gel,n-hexane:ethyl acetate=1:1) to obtain Compound 7a (37 mg, 75%).

¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 8.19 (d, J=5.1 Hz, 1H),7.86-7.77 (m, 3H), 7.77-7.68 (m, 1H), 7.58-7.47 (m, 3H), 7.36 (d, J=2.5Hz, 1H), 6.99 (dd, J=8.9, 2.5 Hz, 1H), 6.47-5.97 (m, 1H), 5.43 (s, 1H),3.89 (s, 3H), 3.32 (m, 1H), 1.66 (m, 2H), 1.43 (m, 3H), 1.30-1.15 (m,2H), 1.09-0.90 (m, 3H).

In the same manner as in Preparation Example 1-24, the compounds ofPreparation Examples 1-25 to 1-30 were obtained (Compound 7b (35 mg,67%), 7c (28 mg, 53%), 7d (35 mg, 53%), 7e (37 mg, 54%), 7f (34 mg,65%), 7g (27 mg, 43%)).

<Preparation Example 1-25>N-cyclohexyl-4-(5-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(7b)

¹H NMR (400 MHz, CDCl₃) δ 8.25 (m, 3H), 7.82 (d, J=8.1 Hz, 1H), 7.74 (d,J=8.1 Hz, 1H), 7.68-7.62 (m, 1H), 7.60-7.51 (m, 2H), 7.38 (d, J=2.4 Hz,1H), 7.02 (dd, J=8.9, 2.4 Hz, 1H), 6.52 (s, 1H), 3.89 (s, 3H), 3.68-3.17(s, 1H), 1.45 (m, 5H), 1.26 (m, 2H), 1.18-0.90 (m, 4H).

<Preparation Example 1-26>N-cyclohexyl-4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(7c)

¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J=5.3 Hz, 1H), 7.67 (d, J=9.0 Hz,1H), 7.33 (d, J=1.8 Hz, 1H), 7.14 (s, 1H), 7.08-7.04 (m, 1H), 6.94 (dd,J=9.0, 2.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 4.28 (d, J=5.1Hz, 2H), 4.25 (d, J=5.1 Hz, 2H), 3.87 (s, 3H), 3.74-3.57 (m, 1H), 1.87(m, 1H), 1.71 (m, 2H), 1.61 (m, 1H), 1.35 (m, 3H), 1.19 (m, 4H).

<Preparation Example1-27>4-(2-(benzofuran-5-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-cyclohexylpyrimidin-2-amine(7d)

¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J=1.6 Hz, 1H), 7.99 (dd, J=8.7, 1.6Hz, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.83 (d, J=2.3 Hz, 1H), 7.61 (d, J=8.7Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 6.98-6.93 (m, 2H), 6.78 (dd, J=8.6, 2.3Hz, 1H), 6.29 (d, J=7.2 Hz, 1H), 4.17-4.04 (m, 2H), 3.96 (s, 2H),3.84-3.77 (m, 1H), 3.72 (m, 2H), 2.24 (m, 1H), 1.98-1.84 (m, 2H),1.80-1.70 (m, 1H).

<Preparation Example 1-28>N-cyclohexyl-4-(2-(3,4-dichlorophenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(7e)

¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J=5.3 Hz, 1H), 7.79 (s, 1H), 7.60 (d,J=9.0 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.35-7.29 (m, 2H), 6.98 (dd,J=9.0, 2.4 Hz, 1H), 6.56-6.19 (s, br, 1H), 6.17-5.61 (s, br, 1H), 3.88(s, 3H), 1.77-1.56 (m, 5H), 1.26-1.01 (m, 6H).

<Preparation Example 1-29>N-cyclohexyl-4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(7f)

¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=4.8 Hz, 1H), 7.97 (d, J=5.3 Hz,1H), 7.69 (s, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.22(m, 1H), 6.99 (dd, J=7.0, 2.0 Hz, 1H), 6.49 (s, 1H), 3.89 (s, 3H), 3.36(s, 1H), 2.03 (m, 1H), 1.67 (m, 4H), 1.58 (m, 1H), 1.31 (m, 1H), 1.15(m, 4H).

<Preparation Example1-30>4-(2-(benzo[d][1,3]dioxole-5-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-cyclohexylpyrimidin-2-amine(7g)

¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=5.3 Hz, 1H), 7.67 (d, J=8.6 Hz,1H), 7.56-7.40 (m, 1H), 7.28 (d, J=Hz, 1H), 5.99 (s, 2H), 3.86 (s, 3H),3.73-3.40 (s, 1H), 2.16-1.84 (m, 2H), 1.81-1.57 (m, 3H), 1.26 (s, 6H).2.3 Hz, 1H), 7.09-7.04 (m, 2H), 6.94 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d,J=8.1)

<Preparation Example 1-31> (S)-tert-butyl3-((4-(5-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(8a)

Compound 5a (218 mg, 0.506 mmol) and (S)-tert-butyl3-aminopiperidine-1-carboxylate (199 μl) were dissolved in THF (3.4 ml)and stirred at 60° C. for 12 hours. After confirming the completion ofthe reaction, the reaction mixture was cooled to ambient temperature andthe filtrate was distilled under reduced pressure, and the residue waspurified by column chromatography (silica gel, n-hexane:ethylacetate=1:1) to obtain Compound 8a (138 mg, 50%).

¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.18 (d, J=5.0 Hz, 1H), 7.85(dd, J=18.9, 9.1 Hz, 3H), 7.78 (d, J=7.4 Hz, 1H), 7.58-7.49 (m, 3H),7.38 (d, J=2.3 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 6.22 (d, J=60.2 Hz, 1H),3.90 (s, 3H), 3.75-3.50 (m, 2H), 3.39 (s, 1H), 3.31-3.13 (m, 2H),2.16-1.89 (m, 1H), 1.43 (s, 9H), 1.32-1.22 (m, 3H), 0.97-0.79 (m, 1H).

In the same manner as in Preparation Example 1-31, the compounds ofPreparation Examples 1-32 to 1-37 were obtained. (Compound 8b (100 mg,50%), 8c (142 mg, 74%), 8d (130 mg, 66%), 8e (121 mg, 73%), 8f (143 mg,73%), 8g (69 mg, 50%)).

<Preparation Example 1-32> (S)-tert-butyl3-((4-(5-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(8b)

¹H NMR (400 MHz, CDCl₃) δ 8.28 (m, J=8.4 Hz, 3H), 7.82 (d, J=8.0 Hz,1H), 7.70 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.64-7.52 (m, 2H), 7.37 (d,J=2.3 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.49 (d, J=5.4 Hz, 1H), 3.89 (s,3H), 3.70 (s, 1H), 3.60-3.31 (m, 2H), 3.15 (m, 2H), 1.52 (m, 2H),1.50-1.43 (m, 3H), 1.42-1.26 (s, 9H).

<Preparation Example 1-33> (S)-tert-butyl3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(8c)

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=5.0 Hz, 1H), 7.69 (d, J=8.5 Hz,1H), 7.31 (s, 1H), 7.14 (s, 1H), 7.04 (d, J=7.9 Hz, 1H), 6.96 (d, J=2.0Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.23 (s, 1H), 4.28 (d, J=4.9 Hz, 2H),4.24 (d, J=4.9 Hz, 2H), 3.86 (s, 3H), 3.78 (s, 1H), 3.45 (m, 2H), 3.37(m, 1H), 1.66 (m, 2H), 1.53 (m, 2H), 1.43 (s, 9H), 1.23 (m, 2H).

<Preparation Example 1-34> (S)-tert-butyl3-((4-(2-(benzofuran-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(8d)

¹H NMR (400 MHz, CDCl₃) δ 8.12 (m, 2H), 7.71 (dd, J=7.2, 3.4 Hz, 2H),7.61-7.48 (m, 3H), 7.03 (m, 1H), 6.87 (d, J=1.6 Hz, 1H), 6.29 (s, 1H),3.91 (s, 3H), 3.85-3.42 (m, 3H), 3.27 (s, 2H), 1.73 (m, 3H), 1.44 (m,9H), 1.12-0.78 (m, 1H).

<Preparation Example 1-35> (S)-tert-butyl3-((4-(2-(3,4-dichlorophenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(8e)

¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J=5.2 Hz, 1H), 7.77 (d, J=2.0 Hz,1H), 7.60 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.27-7.24 (m, 2H),6.94 (d, J=2.5 Hz, 1H), 6.40-6.14 (m, 1H), 3.83 (s, 3H), 3.68-3.52 (s,1H), 3.45 (m, 1H), 3.30 (s, 1H), 3.25 (m, 2H), 1.63 (m, 2H), 1.41 (s,9H), 1.32-1.23 (m, 2H).

<Preparation Example 1-36> (S)-tert-butyl3-((4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(8f)

¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.69 (s,1H), 7.63 (s, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.22 (m, 1H), 7.06-6.95 (m,1H), 6.32 (s, 1H), 3.87 (s, 3H), 3.63 (m, 1H), 3.45 (s, 1H), 3.26 (m,2H), 2.01-1.81 (m, 1H), 1.68 (m, 2H), 1.52-1.34 (s, 9H), 1.25 (m, 2H),0.85 (m, 1H).

<Preparation Example 1-37> (S)-tert-butyl3-((4-(2-(benzo[d][1,3]dioxole-5-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(8g)

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 7.00(m, 3H), 6.87 (s, 1H), 6.45 (s, 1H), 6.02 (s, 2H), 4.08 (s, 1H), 3.85(s, 3H), 3.62 (s, 1H), 3.35 (m, 1H), 2.99 (m, 2H), 2.00 (m, 2H), 1.71(m, 3H), 1.23 (m, 1H).

<Example1-1>2-(naphthalene-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol(9a)

Compound 6a (24 mg, 0.053 mmol) was dissolved in methylene chloride (0.5ml), BBr₃ (25 μl) was added at −78° C., stirred for about 1 hour, andthen stirred at room temperature for about 2 hours. After confirming thecompletion of the reaction, methanol was added and quenched. The organicsolvent was distilled under reduced pressure, extracted with methylenechloride, and washed with a saturated NaHCO₃aqueous solution. Theextracted organic layer was dried over magnesium sulfateanhydrous,filtered, and the filtrate was distilled under reduced pressure, and theresidue was purified by column chromatography (silica gel, methylenechloride:MeOH=20:1) to obtain Compound 9a (20 mg, 86%).

¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), 8.20 (d, J=1.6 Hz, 1H),7.76-7.85 (m, 3H), 7.63 (s, 1H), 7.49-7.54 (m, 3H), 7.36 (d, J=2.4 Hz,1H), 6.98 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.34 (br, s, 1H), 5.34 (d, J=7.6Hz, 1H), 3.89 (s, 3H), 3.49-3.62 (m, 2H), 3.24-3.42 (m, 1H), 2.80-3.03(m, 2H), 1.07-1.46 (m, 2H).

In the same manner as in Example 1-1, the compounds of Examples 1-2 to1-5 were obtained (Compound 9b (19 mg, 59%), 9c (13 mg, 36%), 9d (30 mg,93%), 9f (10 mg, 30%)).

<Example1-2>2-(quinoline-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol(9b)

<Example1-3>2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol(9c)

¹H NMR (400 MHz, MeOD) δ 8.17 (d, J=8.9 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H),7.21 (d, J=2.1 Hz, 1H), 7.15-7.08 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.93(dd, J=8.9, 2.4 Hz, 1H), 6.33 (d, J=7.2 Hz, 1H), 4.35-4.30 (m, 4H),4.09-4.01 (s, 1H), 3.68 (m, 1H), 2.47-2.34 (m, 2H), 2.28-2.20 (m, 1H),2.13-1.98 (m, 3H), 1.55 (m, 1H), 1.29 (m, 2H).

<Example1-4>2-(benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol(9d)

¹H NMR (400 MHz, CD₃OD) δ 8.27 (d, J=1.6 Hz, 1H), 7.99 (dd, J=8.7, 1.6Hz, 1H), 77.84 (d, J=4.5 Hz, 1H), 7.83 (d, J=2.3 Hz, 1H), 7.61 (d, J=8.7Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 6.98-6.93 (m, 2H), 6.78 (dd, J=8.6, 2.3Hz, 1H), 6.29 (d, J=7.2 Hz, 1H), 4.17-4.04 (m, 2H), 3.96 (s, 2H),3.84-3.77 (m, 1H), 3.72 (m, 2H), 2.24 (m, 1H), 1.98-1.84 (m, 2H),1.80-1.70 (m, 1H).

<Example1-5>2-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol(9f)

¹H NMR (400 MHz, CD₃OD) δ 8.40 (dd, J=6.7, 2.0 Hz, 1H), 8.32 (m, 1H),7.94 (d, J=7.2 Hz, 1H), 7.55-7.49 (m, 1H), 7.44 (d, J=8.7 Hz, 1H), 6.97(s, 1H), 6.82 (dd, J=8.7, 2.3 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 4.25-4.13(m, 2H), 3.91-3.82 (s, 1H), 3.81-3.73 (m, 2H), 2.36-2.27 (m, 1H),2.02-1.91 (m, 2H), 1.84-1.74 (m, 1H), 1.29 (m, 1H), 1.07-0.78 (m, 1H).

<Example1-6>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-5-ol(10a)

Compound 7a (37 mg, 0.082 mmol) was dissolved in methylene chloride (0.8ml), BBr₃ (39 al) was added at −78° C., stirred for about 1 hour, andthen stirred at room temperature for about 2 hours. After confirming thecompletion of the reaction, methanol was added and quenched. The organicsolvent was distilled under reduced pressure, extracted with methylenechloride, and washed with a saturated NaHCO₃aqueous solution. Theextracted organic layer was dried over magnesium sulfateanhydrous,filtered, and the filtrate was distilled under reduced pressure, and theresidue was purified by column chromatography (silica gel, methylenechloride:MeOH=20:1) to obtain Compound 10a (21 mg, 58%).

¹H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.40 (s, 1H), 8.21 (s, 1H),7.95-8.00 (m, 2H), 7.52-7.80 (m, 4H), 7.29 (s, 1H), 7.14 (s, 1H), 6.87(dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.71 (s, 1H), 5.22 (br, s, 1H), 2.90 (br,s, 1H), 1.15-1.25 (m, 6H), 0.67-0.91 (m, 4H).

In the same manner as in Example 1-6, the compounds of Examples 1-7 to1-11 were obtained (Compound 10b (17 mg, 51%), 10c (13 mg, 53%), 10d (20mg, 60%), 10e (10 mg, 54%), 10f (20 mg, 74%)).

<Example1-7>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-5-ol(10b)

¹H NMR (400 MHz, CD₃OD) δ 8.44 (t, J=8.7 Hz, 1H), 8.37 (t, J=5.5 Hz,1H), 8.05 (s, 1H), 7.98-7.92 (m, 1H), 7.71 (dd, J=9.9, 5.1 Hz, 2H),7.68-7.54 (m, 2H), (d, J=2.1 Hz, 1H), 7.00-6.93 (m, 1H), 6.74 (s, 1H),3.35 (s, 1H), 2.85 (s, 1H), 1.57-1.34 (m, 3H), 1.32-1.09 (m, 3H),1.07-0.72 (m, 5H).

<Example1-8>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazole-5-ol(10c)

¹H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 8.39 (m, 1H), 7.44 (s, 1H), 7.05(s, 1H), 6.96 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.78 (dd, J=8.8, 2.3 Hz,1H), 6.60 (s, 1H), 4.25 (s, 4H), 3.22 (s, 1H), 1.92 (m, 1H), 1.57 (m,3H), 1.25 (m, 3H), 1.07 (m, 4H), 0.86 (m, 1H).

<Example1-9>2-(benzofuran-5-yl)-1-(2-(cyclohexylamine)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol(10d)

¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 1H), 7.83 (s, 2H), 7.55 (d, J=8.5 Hz,2H), 7.42 (d, J=8.3 Hz, 1H), 7.14 (d, J=2.1 Hz, 1H), 6.96-6.85 (m, 2H),6.53 (s, 1H), 4.16-3.53 (m, 1H), 3.15 (s, 1H), 1.51 (s, 5H), 1.26 (s,1H), 1.18-0.82 (m, 5H).

<Example1-10>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazole-5-ol(10e)

¹H NMR (400 MHz, DMSO-d6) δ 9.34 (1H, s), 8.10 (1H, d, J=5.6 Hz), 7.82(1H, d, J=2.0 Hz), 7.70 (1H, d, J=8.4 Hz), 7.44 (1H, dd, J=8.4 Hz, J=2.4Hz), 7.19 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=2.4 Hz), 6.83 (1H, dd, J=8.8Hz, J=2.4 Hz), 6.71 (1H, d, J=7.6 Hz), 6.45 (1H, dd, J=5.6 Hz, J=1.6Hz), 6.38 (1H, d, J=1.6 Hz), 3.61 (2H, s), 1.83-1.85 (2H, m), 1.66-1.70(2H, m), 1.55-1.59 (1H, m), 1.23-1.32 (3H, m), 1.10-1.19 (3H, m)

<Example1-11>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-5-ol(10f)

¹H NMR (400 MHz, CD₃OD) δ 8.40 (dd, J=6.6, 2.0 Hz, 1H), 8.31 (m, 1H),7.85 (m, 1H), 7.62-7.47 (m, 2H), 7.44 (d, J=8.7 Hz, 1H), 6.97 (d, J=2.0Hz, 1H), 6.82 (dd, J=8.7, 2.3 Hz, 1H), 3.72 (s, 1H), 1.98-1.93 (m, 1H),1.76 (m, 2H), 1.70-1.49 (m, 4H), 1.18-1.08 (m, 2H), 0.91-0.82 (m, 3H).

<Example 1-12>(S)-4-(5-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(11a)

Compound 8a (377 mg, 0.61 mmol) was dissolved in 1,4-dioxane (6.1 ml)and 4 M−HCl (3 ml) containing 1,4-dioxane was treated at roomtemperature. The reaction mixture was stirred at room temperature for 20minutes, the mixture was diluted with ether and then stirred until theproduct separated to a solid. The solid product was filtered off andwashed with ether followed by hexane. The crude product was thencrystallized to obtain Compound 11a (290 mg, 65%).

¹H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 7.97 (d, J=5.2 Hz, 3H), 7.72 (m,2H), 7.64-7.53 (m, 3H), 7.35 (s, 1H), 7.00 (s, 1H), 6.64 (s, 1H), 3.85(s, 3H), 3.37 (s, 1H), 3.17-2.88 (m, 2H), 2.86-2.57 (m, 2H), 1.89 (m,2H), 1.20 (m, 3H).

In the same manner as in Example 1-12, the compounds of Examples 1-13 to1-18 were obtained (Compound 11b (47 mg, 61%), 11c (54 mg, 73%), 11d,11e (71 mg, 83%), 11f (50 mg, 67%), 11g (41 mg, 92%)).

<Example 1-13>(S)-4-(5-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(11b)

¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=7.8 Hz, 2H), 8.08 (s, 1H), 7.97 (d,J=8.0 Hz, 1H), 7.72 (s, 2H), 7.62 (s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.33(s, 1H), 7.06 (d, J=8.9 Hz, 1H), 6.76 (s, 1H), 3.87 (s, 3H), 3.84 (s,1H), 3.62 (s, 1H), 3.19 (s, 1H), 3.06 (m, 1H), 2.88 (m, 1H), 2.74 (m,1H), 1.81 (m, 2H), 1.63-1.25 (m, 3H).

<Example 1-14>(S)-4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(11c)

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.52 (s, 1H), 7.22 (s, 1H), 6.99(s, 1H), 6.90 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 1H), 6.46 (s, 1H),4.22 (d, J=4.8 Hz, 2H), 4.20 (d, J=4.8 Hz, 2H), 3.99 (s, 1H), 3.81 (s,3H), 3.57 (s, 1H), 3.24 (m, 1H), 3.03-2.85 (m, 2H), 1.97 (m, 2H), 1.66(m, 3H), 1.22 (m, 1H).

<Example 1-15>(S)-4-(2-(benzofuran-5-yl)-5-methoxy-H-benz[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(11d)

¹H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.12 (s, 1H), 8.01 (d, J=2.0 Hz,1H), 7.91 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.41(s, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.07 (s, 1H), 6.75 (s, 1H), 4.31 (s,1H), 3.98 (m, 3H), 3.72-3.51 (m, 1H), 3.28-3.18 (m, 1H), 2.98 (m, 2H),2.02 (s, 1H), 1.86 (m, 1H), 1.73 (m, 3H), 1.29 (m, 1H).

<Example 1-16>(S)-4-(2-(3,4-dichlorophenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(11e)

¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.61 (d,J=8.3 Hz, 2H), 7.45-7.40 (m, 1H), 7.27 (d, J=1.4 Hz, 1H), 7.02 (d, J=8.3Hz, 1H), 6.69 (s, 1H), 3.86 (s, 3H), 3.35 (s, 1H), 3.15-2.85 (m, 3H),2.14-1.90 (m, 2H), 1.65 (m, 4H), 1.20 (m, 1H).

<Example 1-17>(S)-4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(11f)

¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J=4.8 Hz, 1H), 7.92 (d, J=5.7 Hz,1H), 7.85 (s, 1H), 7.63 (s, 1H), 7.47 (m, 1H), 7.25 (d, J=2.2 Hz, 1H),7.03 (d, J=8.2 Hz, 1H), 6.65 (s, 1H), 3.95 (s, 1H), 3.87 (s, 3H), 3.26(s, 1H), 3.01-2.84 (m, 2H), 2.19-1.91 (m, 2H), 1.91-1.53 (m, 3H),1.53-1.22 (m, 1H), 1.21-0.47 (m, 1H).

<Example 1-18>(S)-4-(2-(benzo[d][1,3]dioxole-5-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(11g)

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 7.00(m, 3H), 6.87 (s, 1H), 6.45 (s, 1H), 6.02 (s, 2H), 4.08 (s, 1H), 3.85(s, 3H), 3.62 (s, 1H), 3.35 (m, 1H), 2.99 (m, 2H), 2.00 (m, 2H), 1.71(m, 3H), 1.23 (m, 1H).

<Example 1-19>(S)-cyclopropyl(3-((4-(5-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(12a)

Compound 11a (100 mg, 0.22 mmol) was dissolved in THF (0.55 ml) andcooled to 0° C., then treated with TEA (46 μL). The mixture was addedcyclopropanecarbonyl chloride (23 mg) at 0° C., raised to roomtemperature, and stirred for 1 hour. The reaction mixture wasconcentrated in vacuum, diluted with methylene chloride and washed withwater and saturated aqueous sodium chloride solution. The organic layerwas dried over sodium sulfate, filtered, and the filtrate was distilledunder reduced pressure, and the residue was purified by columnchromatography (silica gel, DCM:MEOH 40:1) to obtain Compound 12a (73mg, 64%).

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 2H), 7.81 (m, 4H), 7.577.47 (m, 3H),7.32 (s, 1H), 7.01 (dd, J=8.8, 2.2 Hz, 1H), 6.36 (m, 1H), 4.04 (s, 1H),3.86 (s, 3H), 3.74 (m, 1H), 3.46 (m, 2H), 3.10 (m, 1H), 1.59 (m, 4H),1.33-1.12 (m, 1H), 1.05-0.70 (m, 4H), 0.44 (s, 1H).

In the same manner as in Example 1-19, the compound of Examples 1-20 to1-25 was obtained (Compound 12b (41 mg, 79%), 12c (48 mg, 77%), 12d, 12e(60 mg, 78%), 12f (32 mg, 61%), 12g (37 mg, 84%)).

<Example 1-20>(S)-cyclopropyl(3-((4-(5-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(12b)

¹H NMR (400 MHz, CD₃OD) δ 8.43 (d, J=8.5 Hz, 1H), 8.42-8.34 (m, 1H),8.18 (d, J=8.5 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.69 (dd, J=13.5, 6.1Hz, 2H), 7.61 (dd, J=12.6, 5.5 Hz, 2H), 7.32 (s, 1H), 7.05 (d, J=8.9 Hz,1H), 6.77 (s, 1H), 4.18-4.06 (br, 1H), 3.97 (m, 1H), 3.89 (s, 3H), 3.13(m, 1H), 2.86 (m, 2H), 1.91 (m, 1H), 1.48 (m, 4H), 1.22-1.03 (m, 1H),0.93-0.48 (m, 4H), 0.15 (m, 1H).

<Example 1-21>(S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(12c)

¹H NMR (400 MHz, CD₃OD) δ 8.32 (d, J=33.2 Hz, 1H), 7.70-7.44 (m, 1H),7.21 (s, 1H), 7.04 (s, 1H), 6.94 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.48(d, J=33.2 Hz, 1H), 4.25 (d, J=6.6 Hz, 4H), 3.97 (s, 1H), 3.85 (s, 3H),3.52 (m, 1H), 3.31 (m, 1H), 3.03-2.85 (m, 1H), 1.95 (m, 1H), 1.77-1.69(m, 2H), 1.59-1.52 (m, 1H), 1.31 (m, 1H), 0.88 (m, 3H), 0.84-0.68 (m,2H).

<Example 1-22>(S)-(3-(4-(2-(benzofuran-5-yl)-5-methoxy-1H-benz[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone(12d)

¹H NMR (400 MHz, MeOD) δ 8.32 (m, 1H), 7.86 (d, J=2.2 Hz, 2H), 7.74 (d,J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.46 (s, 1H), 7.27 (s, 1H), 7.00(d, J=8.8 Hz, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 4.14 (s, 1H), 3.98 (m,1H), 2.05-1.91 (m, 2H), 1.59-1.52 (m, 3H), 1.33-1.23 (m, 4H), 0.90-0.85(m, 5H).

<Example 1-23>(S)-cyclopropyl(3-((4-(2-(3,4-dichlorophenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(12e)

¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.76 (d, J=22.0 Hz, 1H), 7.60(d, J=30.5 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.30 (d, J=2.2 Hz, 2H), 6.97(s, 1H), 6.47-6.16 (m, 1H), 4.01 (s, 1H), 3.86 (s, 3H), 3.46 (m, 1H),3.18 (m, 1H), 1.74 (m, 2H), 1.61-1.52 (m, 2H), 1.52-1.44 (m, 1H), 1.40(m, 1H), 1.23 (m, 1H), 0.98-0.92 (m, 1H), 0.89-0.71 (m, 4H).

<Example 1-24>(S)-cyclopropyl(3-((4-(2-(4-fluoro-3-(trifluoro)phenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(12f)

¹H NMR (400 MHz, CD₃OD) δ 8.50-8.39 (m, 1H), 7.95 (s, 1H), 7.81 (s, 1H),7.65 (m, 1H), 7.44 (m, 1H), 7.27 (s, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.76(s, 1H), 4.12-4.01 (s, 1H), 3.88 (s, 3H), 3.27-3.14 (m, 1H), 3.07-2.93(m, 1H), 2.82 (s, 1H), 1.93 (m, 1H), 1.81-1.69 (m, 2H), 1.62-1.51 (m,2H), 1.30 (m, 1H), 0.88 (m, 3H), 0.81 (m, 2H).

<Example 1-25>(S)-(3-((4-(2-(benzo[d][1,3]dioxole-5-yl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)(cyclopropyl)methanone(12g)

¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.63 (d, J=32.3 Hz, 1H), 7.33(s, 1H), 7.06 (d, J=24.5 Hz, 2H), 6.95 (d, J=7.2 Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 6.26 (d, J=32.3 Hz, 1H), 6.01 (s, 2H), 4.15-4.04 (s, 1H), 3.87(s, 3H), 3.82-3.71 (m, 1H), 3.56-3.26 (m, 2H), 1.89-1.71 (m, 2H),1.67-1.54 (m, 3H), 1.03-0.96 (m, 3H), 0.88-0.80 (m, 3H).

<Example 1-26>(S)-cyclopropyl(3-((4-(5-hydroxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(13a)

Compound 12a (66 mg, 0.127 mmol) was dissolved in methylene chloride(1.3 ml), BBr₃ (60 al) was added at −78° C. and stirred for about 1hour, and then stirred at room temperature for about 2 hours. Afterconfirming the completion of the reaction, methanol was added andquenched. The organic solvent was distilled under reduced pressure,extracted with methylene chloride, and washed with a saturatedNaHCO₃aqueous solution. The extracted organic layer was dried overmagnesium sulfate anhydrous, filtered, and the filtrate was distilledunder reduced pressure and the residue was purified by columnchromatography (silica gel, methylene chloride:MeOH=20:1) to obtainCompound 13a (39 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.42-8.18 (m, 2H), 7.96-7.94(m, 3H), 7.61-7.54 (m, 5H), 7.11 (d, J=2.4 Hz, 1H), 6.84 (d, J=7.6 Hz,1H), 6.67-6.25 (m, 1H), 4.78 (s, 1H), 4.14-3.84 (m, 2H), 3.17-2.85 (m,2H), 1.97-1.91 (m, 2H), 1.75 (s, 1H), 1.45-1.14 (m, 4H), 0.85-0.69 (m,2H).

In the same manner as in Example 1-26, the compounds of Examples 1-27 to1-32 were obtained (Compound 13b (6 mg, 30%), 13c (22 mg, 52%), 13d, 13e(8 mg, 41%) 13f (14 mg, 50%), 13g).

<Example 1-27>(S)-cyclopropyl(3-((4-(5-hydroxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(13b)

¹H NMR (400 MHz, CD₃OD) δ 8.49-8.41 (m, 2H), 8.19 (d, J=8.5 Hz, 1H),7.95 (d, J=7.5 Hz, 1H), 7.74-7.67 (m, 2H), 7.61 (m, 2H), 6.95 (dd,J=8.5, 2.1 Hz, 2H), 6.76 (s, 1H), 4.02 (s, 1H), 3.18 (s, 1H), 2.06-1.93(m, 1H), 1.60 (m, 3H), 1.39 (m, 4H), 1.29 (m, 4H), 0.97-0.78 (m, 5H),0.60 (m, 1H).

<Example 1-28>(S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(13c)

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 7.63-7.41 (m, 1H), 7.09 (s, 1H),7.03 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.92-6.82 (m, 2H), 6.57 (s, 1H),4.26 (d, J=6.3 Hz, 4H), 4.07 (s, 1H), 3.49 (s, 1H), 2.97 (m, 1H), 2.02(m, 2H), 1.79 (m, 2H), 1.61 (m, 4H), 0.95-0.79 (m, 3H), 0.69 (m, 2H).

<Example 1-29>(S)-(3-(4-(2-(benzofuran-5-yl)-5-hydroxy-1H-benz[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone(13d)

¹H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 8.33 (d, J=47.4 Hz, 1H), 8.07 (s,1H), 7.87 (d, J=23.5 Hz, 1H), 7.65 (s, 2H), 7.45 (d, J=18.7 Hz, 1H),7.08 (d, J=2.2 Hz, 1H), 7.02 (s, 1H), 6.82 (d, J=7.4 Hz, 1H), 4.08 (s,1H), 2.95 (s, 1H), 1.95 (m, 2H), 1.76 (m, 2H), 1.56 (m, 2H), 1.23 (m,2H), 0.89-0.66 (m, 4H), 0.63-0.54 (m, 1H), 0.23 (m, 1H).

<Example 1-30>(S)-cyclopropyl(3-((4-(2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(13e)

¹H NMR (400 MHz, MeOD) δ 8.43 (d, J=18.2 Hz, 1H), 7.76 (s, 1H), 7.59 (m,2H), 7.40 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 6.92 (d, J=8.7 Hz, 1H), 6.78(s, 1H), 4.20 (s, 1H), 4.08 (m, 1H), 3.15 (m, 1H), 2.92 (s, 1H),2.06-1.93 (m, 1H), 1.83 (m, 2H), 1.57 (m, 3H), 1.28 (m, 1H), 0.92-0.77(m, 3H), 0.65 (m, 1H), 0.36 (m, 1H).

<Example 1-31>(S)-cyclopropyl(3-((4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(13f)

¹H NMR (400 MHz, CD₃OD) δ 8.49-8.37 (m, 1H), 7.92 (s, 1H), 7.80 (s, 1H),7.64-7.49 (m, 1H), 7.45 (d, J=9.5 Hz, 1H), 7.14 (s, 1H), 6.92 (d, J=8.8Hz, 1H), 6.77 (s, 1H), 4.19 (s, 1H), 2.93-2.72 (m, 1H), 2.05 (m, 1H),1.91-1.73 (m, 3H), 1.72-1.64 (m, 1H), 1.61-1.50 (m, 2H), 0.94-0.85 (m,2H), 0.84-0.78 (m, 2H), 0.74 (m, 1H), 0.62 (m, 1H).

<Example 1-32>(S)-(3-(4-(2-(benzo[d][1,3]dioxole-5-yl)-5-hydroxy-1H-benz[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone(13g)

¹H NMR (400 MHz, MeOD) δ 8.41-8.25 (m, 1H), 7.55 (m, 1H), 7.08 (s, 1H),6.94 (s, 1H), 6.90-6.77 (m, 3H), 6.49 (m, 1H), 4.25 (s, 1H), 4.02 (m,1H), 3.59-3.36 (m, 1H), 3.08 (m, 2H), 2.06-1.86 (m, 2H), 1.77 (s, 1H),1.61 (m, 3H), 1.29 (m, 1H), 0.90-0.57 (m, 4H), 0.28 (m, 1H).

II. Synthesis of benzimidazole-6-ol derivatives <Preparation Example2-1> N-(5-methoxy-2-nitrophenyl)-2-(methylthio)pyrimidin-4-amine (15)

4-methoxy 2-nitrobezene amine (Compound 14; 4.6 g, 27.11 mmol) wasdissolved in DMF (136 ml) and 60% NaH (1.63 g) was added slowly at 0° C.The mixture was stirred for 1 hour, again,4-chloro-2-(methylthio)pyrimidine (4355 mg, 17.85 mmol) was added andstirred for about 2 hours. Then, the solvent was poured into iced waterto precipitate, and the precipitated reaction was filtered to obtainCompound 15 (6 g, 77%).

¹H NMR (400 MHz, CDCl₃) δ 10.65 (s, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.26(d, J=5.7 Hz, 1H), 8.22 (d, J=9.5 Hz, 1H), 6.59 (dd, J=9.5, 2.7 Hz, 1H),6.50 (d, J=5.7 Hz, 1H), 3.93 (s, 3H), 2.57 (s, 3H).

<Preparation Example2-2>5-methoxy-N-(2-(methylthio)pyrimidin-4-yl)bezene-1,2-diamine (16)

Compound 15 (3 g, 10.22 mmol) was dissolved in methanol (68 ml), then10% Pd/C (448 mg) was added and stirred at room temperature underhydrogen gas for 5 hours. After the reaction was terminated, the mixturewas filtered through celite and the filtrate was distilled under reducedpressure. Compound 16 (2.9 g, 99%) was obtained from the residue withoutany purification.

¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=5.9 Hz, 1H), 7.02 (s, 1H), 6.78 (d,J=2.8 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.68 (dd, J=8.7, 2.8 Hz, 1H),6.07 (d, J=5.9 Hz, 1H), 3.78 (s, 2H), 3.69 (s, 3H), 2.46 (d, J=5.1 Hz,3H).

<Preparation Example2-3>6-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazole(17a)

Compound 16 (160 mg, 0.61 mmol), 2-naphthaldehyde (105 mg, 0.67 mmol),and Na₂S₂O₅ (580 mg) were dissolved in DMF (2 ml) and stirred inmicrowave at 120° C., 150 W, 1 hour 30 minutes. After confirming thecompletion of the reaction, the solvent was poured into iced water toprecipitate. After the precipitated reaction was filtered, the filtratewas distilled under reduced pressure and the residue was purified bycolumn chromatography (silica gel, n-hexane:ethyl acetate=2:1) to obtainCompound 17a (80 mg, 33%).

¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J=5.6 Hz, 1H), 8.65 (d, J=5.6 Hz,1H), 8.22 (d, J=1.2 Hz, 1H), 8.19 (d, J=1.2 Hz, 1H), 7.95-8.00 (m, 6H),7.80 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.54-7.64 (m, 6H), 7.41(d, J=2.4 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.11 (d, J=5.6 Hz, 1H),7.03-7.06 (m, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.28 (s, 3H), 2.27 (s,3H).

In the same manner as in Preparation Example 2-3, the compounds ofPreparation Examples 2-4 to 2-9 were obtained (Compound 17b (300 mg,57%), 17c (423 mg, 63%), 17d (262 mg, 45%), 17e (562 mg, 67%), 17f (370mg, 56%), 17g (414 mg, 64%)).

<Preparation Example2-4>2-(6-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole-2-yl)Quinoline(17b)

¹H NMR (400 MHz, DMSO) δ 9.13 (d, J=5.5 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H),7.76-7.69 (m, 2H), 7.64 (t, J=4.4 Hz, 2H), 7.51-7.47 (m, 1H), 7.06 (dd,J=8.8, 2.4 Hz, 1H), 3.83 (d, J=3.2 Hz, 3H), 3.37 (s, 3H).

<Preparation Example2-5>2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(17c)

¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=5.4 Hz, 1H), 7.68 (d, J=8.8 Hz,1H), 7.42 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 6.96 (m, 2H), 6.85(d, J=8.4 Hz, 1H), 6.54 (d, J=5.4 Hz, 1H), 4.28 (dd, J=3.6, 1.7 Hz, 2H),4.25 (dd, J=3.6, 1.7 Hz, 2H), 3.84 (s, 3H), 2.56 (s, 3H).

<Preparation Example2-6>2-(benzofuran-5-yl)-6-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(17d)

¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=5.4 Hz, 113H), 7.81 (d, J=1.8 Hz,1H), 7.70 (d, J=8.8 Hz, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.48 (d, J=8.6 Hz,1H), 7.43 (d, J=2.5 Hz, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 6.97 (dd,J=8.8, 2.5 Hz, 1H), 16.75 (dd, J=2.2, 0.9 Hz, 1H), 6.44 (d, J=5.4 Hz,1H), 3.83 (s, 3H), 2.49 (s, 3H).

<Preparation Example2-7>2-(3,4-dichlorophenyl)-6-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(17e)

¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=5.3 Hz, 1H), 7.77 (d, J=2.0 Hz,1H), 7.70 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.33 (d, J=2.4 Hz,1H), 7.23 (dd, J=8.3, 2.0 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 6.62(d, J=5.3 Hz, 1H), 3.84 (s, 3H), 2.49 (s, 3H).

<Preparation Example2-8>2-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(17f)

¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=5.3 Hz, 1H), 7.86 (dd, J=6.6, 1.9Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.47 (m, 1H), 7.19 (d, J=2.4 Hz, 1H),7.10 (m, 1H), 6.90 (dd, J=8.8, 2.4 Hz, 1H), 6.59 (d, J=5.3 Hz, 1H), 3.75(s, 3H), 2.33 (s, 3H).

<Preparation Example2-9>2-(benzo[d][1,3]dioxole-5-yl)-6-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole(17g)

¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=5.4 Hz, 1H), 7.70 (d, J=8.8 Hz,1H), 7.43 (d, J=2.4 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H), 7.00 (m, 2H), 6.82(d, J=8.0 Hz, 1H), 6.56 (d, J=5.4 Hz, 1H), 6.03 (s, 2H), 3.86 (s, 3H),2.58 (s, 3H).

<Preparation Example2-10>6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphtalen-2-yl)-1H-benzo[d]imidazole(18a)

Compound 17a (193 mg, 0.48 mg) and Potassium peroxomonosulfate (1.5 g)were dissolved in MeOH:H2O=1:1 mixed solvent (2.5 ml) and stirred atroom temperature for 1 hour. After confirming the reaction, methanol wasdistilled off under reduced pressure. To the distilled mixture wasdiluted by addition of water and stirred until the product separated toa solid. The solid product was filtered off and washed with water andthen the crude product was crystallized to obtain Compound 18a (250 mg,98%).

¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J=5.6 Hz, 1H), 8.26 (d, J=1.6 Hz,1H), 8.01 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.73 (d, J=2.4 Hz,1H), 7.577.65 (m, 3H), 7.47 (d, J=5.6 Hz, 1H), 7.08 (dd, J=8.4 Hz, J=2.4Hz, 1H), 3.85 (s, 3H), 3.30 (s, 3H).

In the same manner as in Preparation Example 2-10, the compounds ofPreparation Examples 2-12 to 2-16 were obtained (Compound 18b (283 mg,98%), 18c (432 mg, 98%), 18d (153 mg, 95%), 18e (526 mg, 98%), 18f (343mg, 96%), 18g (404 mg, 95%)).

<Preparation Example2-11>2-(6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole-2-yl)quinolone(18b)

¹H NMR (400 MHz, DMSO) δ 9.17 (d, J=5.3 Hz, 2H), 8.57-8.53 (m, 2H), 8.37(t, J=7.6 Hz, 2H), 8.02 (d, J=8.0 Hz, 2H), 7.87 (d, J=5.3 Hz, 1H), 7.81(d, J=8.9 Hz, 2H), 7.71 (t, J=7.6 Hz, 2H), 7.62 (t, J=7.4 Hz, 2H),7.37-7.26 (m, 4H), 7.09-7.04 (m, 2H), 3.80 (s, 6H), 2.73 (s, 2H).

<Preparation Example2-12>2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(18c)

¹H NMR (400 MHz, DMSO) δ 9.17 (d, J=5.3 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H),7.60 (d, J=2.0 Hz, 1H), 7.57 (d, J=5.3 Hz, 1H), 7.20 (s, 1H), 7.17 (dd,J=9.0, 2.0 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.99 (s, 1H), 4.33 (s, 2H),4.30 (s, 2H), 3.81 (s, 3H), 2.90 (s, 3H).

<Preparation Example2-13>2-(benzofuran-5-yl)-6-methoxy-1-(2-(methylsufonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(18d)

¹H NMR (400 MHz, DMSO) δ 9.08 (d, J=5.5 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H),7.99 (d, J=1.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.76-7.73 (m, 1H), 7.70(d, J=2.2 Hz, 1H), 7.53 (dd, J=8.8, 1.4 Hz, 1H), 7.45 (d, J=5.5 Hz, 1H),7.13 (dd, J=8.9, 2.3 Hz, 1H), 7.07 (d, J=1.4 Hz, 1H), 3.84 (s, 3H), 3.38(s, 3H).

<Preparation Example2-14>2-(3,4-dichlorophenyl)-6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(18e)

¹H NMR (400 MHz, DMSO) δ 9.13 (d, J=5.5 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H),7.74 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.64 (m, 2H), 7.49 (dd,J=8.4, 2.0 Hz, 1H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 3.83 (s, 3H), 3.37 (s,3H).

<Preparation Example2-15>2-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(18f)

¹H NMR (400 MHz, DMSO) δ 9.15 (d, J=5.5 Hz, 1H), 8.09-8.06 (m, 1H),7.89-7.84 (m, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.63(d, J=2.4 Hz, 1H), 7.58 (d, J=10.2 Hz, 1H), 7.07 (dd, J=8.8, 2.4 Hz,1H), 3.83 (s, 3H), 3.35 (s, 3H).

<Preparation Example2-16>2-(benzo[d][1,3]dioxole-5-yl)-6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole(18g)

¹H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 8.15-8.13 (m, 2H), 7.76 (d, J=7.5Hz, 1H), 7.69-7.50 (m, 2H), 7.21 (s, 1H), 7.17-7.02 (m, 1H), 6.15 (s,2H), 3.83 (s, 3H), 3.44 (s, 3H).

<Preparation Example2-17>4-(6-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(19a)

Compound 18a (41 mg, 0.1 mmol) and tetrahydro-2H-pyran-4-amine (20 ul)were dissolved in THF (1 ml) and stirred at 60° C. for 5 hours. Afterconfirming the completion of the reaction, the reaction mixture wascooled to ambient temperature and the filtrate was distilled underreduced pressure, and the residue was purified by column chromatography(silica gel, n-hexane:ethyl acetate=1:1) to obtain Compound 19a (34 mg,79%).

¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.22 (s, 1H), 7.87-7.83 (m, 1H),7.83-7.76 (m, 3H), 7.54-7.49 (m, 2H), 7.47 (dd, J=8.7, 4.9 Hz, 1H), 7.25(d, J=7.3 Hz, 1H), 7.02 (dd, J=8.8, 2.4 Hz, 1H), 6.56 (s, 1H), 3.86 (s,3H), 3.57 (s, 2H), 3.40 (s, 1H), 2.95 (s, 2H), 1.50-1.33 (m, 2H),1.33-1.07 (m, 3H), 1.03-0.78 (m, 1H).

In the same manner as in Preparation Example 2-17, the compounds ofPreparation Examples 2-18 to 2-23 were obtained (Compound 19b (23 mg,63%), 19c (27 mg, 59%), 19d (36 mg, 70%), 19e (30 mg, 71%), 19f (32 mg,61%), 19g (26 mg, 65%)).

<Preparation Example2-18>4-(6-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(19b)

¹H NMR (400 MHz, CDCl₃) δ8.37 (d, J=5.2 Hz, 1H), 8.21 (s, 2H), 7.78 (s,1H), 7.76 (s, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.63-7.57 (m, 1H), 7.52-7.47(m, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.99 (dd, J=8.1, 2.2 Hz, 1H), 6.61 (s,1H), 5.29 (s, 1H), 3.83 (s, 3H), 3.69 (m, 2H), 3.15 (m, 2H), 1.45-1.40(m, 3H), 0.92 (m, 2H).

<Preparation Example2-19>4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(19c)

¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=4.6 Hz, 1H), 7.71 (d, J=8.8 Hz,1H), 7.24 (s, 1H), 7.10 (s, 1H), 7.01 (dd, J=8.4, 2.0 Hz, 1H), 6.97 (dd,J=8.8, 2.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.37 (s, 1H), 5.69 (s, 1H),4.25 (d, J=4.7 Hz, 2H), 4.24 (d, J=4.7 Hz, 2H), 3.94 (m, 2H), 3.84 (s,3H), 3.42 (m, 2H), 1.83 (m, 1H), 1.52 (m, 2H), 1.26 (m, 2H).

<Preparation Example2-20>4-(2-(benzofuran-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(19d)

¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=4.2 Hz, 1H), 7.89 (d, J=1.3 Hz,1H), 7.76 (d, J=8.8 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.48 (d, J=8.6 Hz,1H), 7.41 (dd, J=8.6, 1.3 Hz, 1H), 7.26 (s, 1H), 7.00 (dd, J=8.8, 2.4Hz, 1H), 6.79 (dd, J=2.2, 0.8 Hz, 1H), 6.42 (s, 1H), 4.04-3.90 (s, 1H),3.84 (s, 3H), 3.83-3.73 (m, 1H), 3.59 (m, 1H), 3.50-3.32 (m, 1H), 3.20(m, 1H), 1.59 (m, 2H), 1.50-1.32 (m, 2H), 1.00-0.80 (m, 1H).

<Preparation Example2-21>4-(2-(3,4-dichlorophenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(19e)

¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J=4.5 Hz, 1H), 7.77 (d, J=1.7 Hz,1H), 7.73 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.28 (dd, J=8.3,1.7 Hz, 1H), 7.16 (s, 1H), 7.00 (dd, J=8.8, 2.4 Hz, 1H), 6.55 (s, 1H),5.56 (s, 1H), 3.90 (m, 2H), 3.85 (s, 3H), 3.54 (m 1H), 3.38-3.27 (m,1H), 1.65 (m 2H), 1.44 (m, 2H), 0.95-0.75 (m, 1H).

<Preparation Example2-22>4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(19f)

¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.84 (d,J=8.7 Hz, 1H), 7.78 (s, 1H), 7.32 (dd, J=15.8, 7.0 Hz, 2H), 7.11 (d,J=8.1 Hz, 1H), 6.63 (s, 1H), 3.98 (s, 1H), 3.95 (s, 3H), 3.71 (s, 1H),3.41 (s, 2H), 1.77 (s, 1H), 1.58 (s, 2H), 1.33 (s, 2H), 0.94 (d, J=9.6Hz, 1H).

<Preparation Example2-23>4-(2-(benzo[d][1,3]dioxole-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(19g)

¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=5.3 Hz, 1H), 7.75 (d, J=8.8 Hz,1H), 7.22 (s, 1H), 7.08 (dd, J=8.1, 1.2 Hz, 1H), 7.04 (d, J=1.2 Hz, 1H),7.00 (dd, J=8.8, 2.4 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.39 (s, 1H), 6.01(s, 2H), 3.96 (d, J=8.1 Hz, 2H), 3.84 (s, 3H), 3.49-3.33 (m, 2H),1.95-1.77 (m, 2H), 1.64-1.47 (m, 3H), 0.95-0.82 (m, 1H).

<Preparation Example 2-24>N-cyclohexyl-4-(6-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(20a)

Compound 18a (40 mg, 0.09 mmol) and cyclohexanamine (22 μl) weredissolved in THF (1 ml) and stirred at 60° C. for 5 hours. Aftercompletion of the reaction, the reaction mixture was cooled to ambienttemperature and the filtrate was distilled under reduced pressure, andthe residue was purified by column chromatography (silica gel,n-hexane:ethyl acetate=1:1) to obtain Compound 20a (29 mg, 69%).

¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 8.16 (d, J=5.3 Hz, 1H),7.87-7.76 (m, 4H), 7.55-7.47 (m, 3H), 7.35 (d, J=2.4 Hz, 1H), 7.02 (dd,J=8.8, 2.4 Hz, 1H), 6.29 (s, 1H), 3.87 (s, 3H), 3.51 (s, 1H), 1.72 (m,2H), 1.53 (m, 3H), 1.24 (m, 1H), 1.09 (m, 4H), 0.92 (m, 1H).

In the same manner as in Preparation Example 2-24, the compounds ofPreparation Examples 2-25 to 2-30 were obtained (Compound 20b (31 mg,98%), 20c (40 mg, 71%), 20d (34 mg, 57%), 20e (20 mg, 50%), 20f (27 mg,46%), 20g (23 mg, 55%)).

<Preparation Example 2-25>N-cyclohexyl-4-(6-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(20b)

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=4.0 Hz, 1H), 8.17 (s, 2H), 7.73(dd, J=8.3, 3.7 Hz, 2H), 7.64 (d, J=7.2 Hz, 1H), 7.59-7.52 (m, 1H),7.49-7.42 (m, 1H), 7.06 (s, 1H), 6.94 (dd, J=8.8, 2.4 Hz, 1H), 6.44 (d,J=4.0 Hz, 1H), 5.28 (s, 1H), 3.79 (s, 3H), 1.56-1.35 (m, 4H), 1.20 (m,2H), 1.07-0.86 (m, 4H), 0.80 (m, 1H).

<Preparation Example 2-26>N-cyclohexyl-4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(20c)

¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=5.2 Hz, 1H), 7.69 (d, J=8.8 Hz,1H), 7.30 (d, J=2.4 Hz, 1H), 7.12 (s, 1H), 7.02 (dd, J=8.4, 2.1 Hz, 1H),6.96 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.22 (s, 1H), 5.58(s, 1H), 4.27 (dd, J=3.6, 1.7 Hz, 2H), 4.24 (dd, J=3.6, 1.7 Hz, 2H),3.84 (s, 3H), 1.94 (m, 1H), 1.70 (m, 2H), 1.62 (m, 1H), 1.24 (m, 6H),0.87 (m, 2H).

<Preparation Example2-27>4-(2-(benzofuran-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-cyclohexylpyrimidin-2-amine(20d)

¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=5.1 Hz, 1H), 7.87 (s, 1H), 7.74 (d,J=8.8 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.44 (dd,J=8.6, 1.6 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.00 (dd, J=8.8, 2.4 Hz,1H), 6.78 (dd, J=2.2, 0.6 Hz, 1H), 6.21 (s, 1H), 3.86 (s, 3H), 3.71-3.52(s, 1H), 1.84 (m, 2H), 1.67 (m, 2H), 1.59 (m, 1H), 1.48-1.28 (m, 1H),1.17 (m, 4H), 1.02-0.77 (m, 1H).

<Preparation Example 2-28>N-cyclohexyl-4-(2-(3,4-dichlorophenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(20e)

¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=5.1 Hz, 1H), 7.79 (s, 1H), 7.73 (d,J=8.8 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.29 (dd, J=8.3, 2.0 Hz, 1H),7.21 (d, J=2.4 Hz, 1H), 7.00 (dd, J=8.8, 2.4 Hz, 1H), 6.41 (s, 1H), 5.54(s, 1H), 3.86 (s, 3H), 1.69 (m, 4H), 1.62 (m, 1H), 1.25 (m, 2H), 1.18(s, 4H).

<Preparation Example 2-29>N-cyclohexyl-4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-amine(20f)

¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 7.96 (d, J=5.1 Hz, 1H), 7.75 (s,1H), 7.67 (s, 1H), 7.22 (m, 2H), 7.02 (dd, J=8.8, 2.2 Hz, 1H), 6.43 (s,1H), 3.86 (s, 3H), 3.39 (s, 1H), 2.03 (m, 1H), 1.69 (m, 3H), 1.59 (m,1H), 1.22 (m, 6H).

<Preparation Example2-30>4-(2-(benzo[d][1,3]dioxole-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-cyclohexylpyrimidin-2-amine(20g)

¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.29 (d,J=2.2 Hz, 1H), 7.09-7.03 (m, 2H), 6.98 (dd, J=8.8, 2.4 Hz, 1H), 6.81 (d,J=8.0 Hz, 1H), 6.23 (s, 1H), 6.00 (s, 2H), 3.84 (s, 3H), 3.81-3.67 (s,1H), 1.98 (m, 2H), 1.72 (m, 2H), 1.62 (m, 1H), 1.24 (m, 6H).

<Preparation Example 2-31> (S)-tert-butyl3-((4-(6-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(21a)

Compound 18a (250 mg, 0.58 mmol) and(S)-tert-butyl-3-aminopiperidine-1-carboxylate (228 μl) were stirred inTHF (4 ml) at 60° C. for 12 hours. After the completion of the reaction,the reaction mixture was cooled to ambient temperature and the filtratewas distilled under reduced pressure. The residue was purified by columnchromatography (silica gel, n-hexane:ethyl acetate=1:1) to obtainCompound 21a (180 mg, 57%).

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=5.2 Hz, 2H), 7.85 (m, 2H), 7.79 (m,2H), 7.56-7.47 (m, 3H), 7.36 (s, 1H), 7.01 (dd, J=8.8, 2.4 Hz, 1H), 6.29(s, 1H), 3.86 (s, 3H), 3.78-3.57 (s, 1H), 3.32 (m, 3H), 1.76-1.52 (m,2H), 1.43 (s, 9H), 1.28 (m, 1H), 1.25 (d, J=7.1 Hz, 2H), 1.17-0.79 (m,1H).

In the same manner as in Preparation Example 2-31, the compounds ofPreparation Examples 2-32 to 2-37 were obtained (Compound 21b (100 mg,50%), 21c (159 mg, 66%), 21d (90 mg, 52%), 21e (210 mg, 55%), 21f (93mg, 50%), 21g (190 mg, 58%)).

<Preparation Example 2-32> (S)-tert-butyl3-((4-(6-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(21b)

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=4.0 Hz, 1H), 8.17 (s, 2H), 7.73(dd, J=8.3, 3.7 Hz, 2H), 7.64 (d, J=7.2 Hz, 1H), 7.59-7.52 (m, 1H),7.49-7.42 (m, 1H), 7.06 (s, 1H), 6.94 (dd, J=8.8, 2.4 Hz, 1H), 6.44 (d,J=4.0 Hz, 1H), 5.28 (s, 1H), 3.79 (s, 3H), 1.56-1.35 (m, 4H), 1.20 (m,2H), 1.07-0.86 (m, 4H), 0.80 (m, 1H).

<Preparation Example 2-33> (S)-tert-butyl3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(21c)

¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J=5.2 Hz, 1H), 7.64 (d, J=8.8 Hz,1H), 7.29 (s, 1H), 7.08 (s, 1H), 6.96 (dd, J=8.4, 1.7 Hz, 1H), 6.91 (dd,J=8.8, 2.2 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 6.19 (s, 1H), 5.88 (s, 1H),4.21 (d, J=6.5 Hz, 2H), 4.17 (d, J=6.5 Hz, 2H), 3.78 (s, 3H), 3.45 (m,1H), 3.20 (m, 2H), 1.67 (m, 1H), 1.47 (m, 3H), 1.35 (s, 9H), 1.20 (m,2H).

<Preparation Example 2-34> (S)-tert-butyl3-((4-(2-(benzofuran-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(21d)

¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.8 Hz,1H), 7.69 (d, J=1.7 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz,1H), 7.33 (s, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.84 (d, J=1.7 Hz, 1H), 6.26(s, 1H), 3.86 (s, 3H), 3.70 (s, 1H), 3.46 (s, 1H), 3.31 (m, 2H), 1.70(m, 2H), 1.48 (m, 2H), 1.45 (m, 2H), 1.42 (s, 9H).

<Preparation Example 2-35> (S)-tert-butyl3-((4-(2-(3,4-dichlorophenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(21e)

¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=4.8 Hz, 1H), 7.78 (s, 1H), 7.70 (d,J=8.8 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.26 (dd, J=8.3, 1.9 Hz, 1H),7.21 (s, 1H), 6.98 (dd, J=8.8, 2.4 Hz, 1H), 6.36 (s, 1H), 5.78 (s, 1H),3.83 (s, 3H), 3.65 (m, 1H), 3.43 (m, 1H), 3.25 (sm, 2H), 1.76-1.61 (m,2H), 1.42 (s, 9H), 1.25 (m, 2H), 1.24 (m, 1H).

<Preparation Example 2-36> (S)-tert-butyl3-((4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(21f)

¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J=4.1 Hz, 1H), 7.93 (d, J=4.1 Hz,1H), 7.70 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.17 (m, 2H), 6.97 (dd,J=8.8, 2.4 Hz, 1H), 6.37 (s, 1H), 5.78 (s, 1H), 3.82 (s, 3H), 3.60 (m,1H), 3.41 (m, 1H), 3.22 (m, 2H), 1.65 (m, 2H), 1.42 (m, 3H), 1.39 (s,9H).

<Preparation Example 2-37> (S)-tert-butyl3-((4-(2-(benzo[d][1,3]dioxole-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(21g)

¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J=5.2 Hz, 1H), 7.63 (d, J=8.8 Hz,1H), 7.26 (d, J=2.9 Hz, 1H), 7.02-6.98 (m, 2H), 6.91 (dd, J=8.8, 2.9 Hz,1H), 6.76 (d, J=8.4 Hz, 1H), 6.19 (s, 1H), 5.95 (s, 2H), 3.78 (s, 3H),3.44 (s, 1H), 3.20 (m, 2H), 1.83 (m, 1H), 1.68 (m, 2H), 1.53-1.45 (m,2H), 1.45-1.31 (s, 9H), 1.21 (m, 2H).

<Example2-1>2-(naphthalene-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol(22a)

Compound 19a (34 mg, 0.076 mmol) was dissolved in methylene chloride(0.8 ml), BBr₃ (0.38 ml) was added at −78° C., and stirred for about 1hour, and then stirred at room temperature for about 2 hours. Afterconfirming the completion of the reaction, methanol was added andquenched. The organic solvent was distilled under reduced pressure,extracted with methylene chloride, and washed with a saturatedNaHCO₃aqueous solution. The extracted organic layer was dried overmagnesium sulfateanhydrous, filtered, and the filtrate was distilledunder reduced pressure, and the residue was purified by columnchromatography (silica gel, methylene chloride:MeOH=20:1) to obtainCompound 22a (20 mg, 60%).

¹H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.47 (s, 1H), 8.16 (s, 1H),7.91-7.97 (m, 3H), 7.39-7.62 (m, 5H), 7.06 (s, 1H), 6.84-6.87 (m, 1H),3.03-3.07 (m, 1H), 2.63-2.67 (m, 1H), 1.98 (d, J=14.0 Hz, 1H), 1.72-1.75(m, 1H), 1.46 (s, 1H), 1.14-1.24 (m, 2H), 1.02-1.10 (m, 2H)

In the same manner as in Example 2-1, the compounds of Examples 2-2 to2-6 were obtained (Compound 22b (17 mg, 77%), 22c (17 mg, 81%), 22d (10mg, 30%), 22e (13 mg, 50%), 22f (9 mg, 51%)).

<Example2-2>2-(Quinoline-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol(22b)

¹H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 8.55-8.45 (m, 2H), 8.24-8.09 (m,1H), 8.01 (d, J=8.0 Hz, 1H), 7.72 (m, 1H), 7.67 (m, 1H), 7.64-7.59 (m,1H), 7.30 (s, 1H), 6.94 (dd, J=13.6, 2.1 Hz, 1H), 6.91-6.86 (m, 1H),3.43 (s, 1H), 2.80 (s, 1H), 1.46 (m, 2H), 1.23 (m, 3H), 0.91 (m, 4H).

<Example2-3>2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol(22c)

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.07 (s,1H), 7.01 (s, 1H), 6.97 (dd, J=8.4, 2.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.64(s, 1H), 4.28 (d, J=5.0 Hz, 2H), 4.26 (d, J=5.0 Hz, 2H), 3.90 (m, 2H),3.62 (s, 1H), 3.39 (s, 1H), 1.29 (m, 4H), 0.91 (m, 3H).

<Example2-4>2-(benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol(22d)

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=7.1 Hz, 1H), 7.97 (d, J=1.5 Hz,1H), 7.91 (d, J=1.5 Hz, 1H), 7.69 (m, 2H), 7.61-7.56 (m, 2H), 6.99-6.95(m, 2H), 6.20 (d, J=7.1 Hz, 1H), 4.28 (m, 2H), 3.99 (s, 1H), 3.86-3.74(m, 2H), 2.43-2.34 (m, 1H), 2.14-2.02 (m, 2H), 1.92-1.72 (m, 2H), 1.28(m, 1H).

<Example2-5>2-(3,4-dichlorophenyl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol(22e)

¹H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.59 (dd,J=8.5, 6.0 Hz, 2H), 7.38 (dd, J=8.5, 2.0 Hz, 1H), 7.08 (s, 1H), 6.96 (s,1H), 6.91 (dd, J=8.7, 2.3 Hz, 1H), 3.87 (m, 2H), 1.81 (s, 2H), 1.46 (m,4H), 1.15 (m, 1H), 1.00-0.74 (m, 2H).

<Example2-6>2-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol(22f)

<Example2-7>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-6-ol(23a)

Compound 20a (28 mg, 0.06 mmol) was dissolved in methylene chloride (0.6ml), BBr₃ (0.3 ml) was added at −78° C. and stirred for about 1 hour,and then stirred at room temperature for about 2 hours. After confirmingthe completion of the reaction, methanol was added and quenched. Theorganic solvent was distilled under reduced pressure, extracted withmethylene chloride, and washed with a saturated NaHCO₃aqueous solution.The extracted organic layer was dried over magnesium sulfate anhydrous,filtered, and the filtrate was distilled under reduced pressure, and theresidue was purified by column chromatography (silica gel, methylenechloride:MeOH=20:1) to obtain Compound 23a (10 mg, 38%).

¹H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.15 (s, 1H,), 7.93-7.95 (m,4H), 7.28-7.62 (m, 5H), 7.07 (s, 1H), 6.85 (dd, J=8.8 Hz, J=2.4 Hz, 1H),6.72 (s, 1H), 2.89 (br, s, 1H), 1.23 (m, 6H), 0.66-0.85 (m, 4H)

In the same manner as in Example 2-7, the compounds of Examples 2-8 to2-13 were obtained (Compound 23b, 23c (23 mg, 78%), 23d (19 mg, 57%),23e (13 mg, 76%), 23f (15 mg, 78%). 23g).

<Example2-8>3-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(Quinoline-2-yl)-3H-benz[d]imidazole-5-ol(23b)

¹H NMR (400 MHz, DMSO) δ 8.52 (m, 2H), 8.18 (s, 1H), 8.03 (dd, J=16.3,7.8 Hz, 1H), 7.76-7.70 (m, 1H), 7.70-7.65 (m, 1H), 7.65-7.59 (m, 1H),7.56-7.40 (m, 1H), 7.29 (s, 1H), 6.92 (dd, J=25.0, 9.5 Hz, 2H), 2.87 (s,1H), 1.99-1.82 (m, 1H), 1.70 (m, 1H), 1.26 (m, 4H), 1.07 (m, 2H), 0.84(m, 4H).

<Example2-9>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazole-6-ol(23c)

¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1H), 7.42 (d, J=8.6 Hz, 1H), 6.98 (s,1H), 6.91 (s, 1H), 6.86 (dd, J=8.4, 2.1 Hz, 1H), 6.77 (dd, J=8.6, 2.4Hz, 2H), 6.46 (s, 1H), 4.17 (d, J=5.1 Hz, 2H), 4.15 (d, J=5.1 Hz, 2H),3.34 (s, 1H), 2.20-1.78 (m, 1H), 1.61 (m, 3H), 1.53 (m, 1H), 1.18 (m,2H), 1.14-0.74 (m, 4H).

<Example2-10>2-(benzofuran-5-yl)-1-(2-(cyclohexylamino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol(23d)

¹H NMR (400 MHz, CD₃OD) δ 8.30 (d, J=1.5 Hz, 1H), 7.85 (dd, J=6.7, 2.2Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.6 Hz, 1H), 7.15 (s, 1H),6.90 (dd, J=10.3, 1.5 Hz, 2H), 6.64 (s, 1H), 3.95-3.81 (m, 1H), 3.56 (s,1H), 2.00 (m, 2H), 1.57 (m, 5H), 0.96-0.81 (m, 4H).

<Example2-11>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazole-6-ol(23e)

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.64 (s, 1H), 7.49 (dd, J=8.5,3.7 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 6.99 (s, 1H), 6.82 (dd, J=8.7, 2.3Hz, 1H), 6.68 (s, 1H), 3.13-2.89 (s, 1H), 1.67-1.39 (m, 6H), 1.04 (m,5H), 0.79 (m, 1H).

<Example2-12>1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-6-ol(23f)

¹H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 8.53-8.45 (m, 1H), 7.83 (d, J=5.5Hz, 1H), 7.61 (dd, J=13.7, 5.5 Hz, 2H), 7.48 (d, J=7.9 Hz, 1H), 7.00 (s,1H), 6.86 (dd, J=9.0, 2.0 Hz, 1H), 2.93 (s, 1H), 1.79 (s, 1H), 1.50 (m,3H), 1.30 (m, 3H), 0.97 (m, 4H), 0.85 (m, 1H).

<Example2-13>2-(benzo[d][1,3]dioxole-5-yl)-3-(2-(cyclohexylamino)pyrimidin-4-yl)-3H-benz[d]imidazole-5-ol(23g)

¹H NMR (400 MHz, MeOD) δ 8.29 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.13 (s,1H), 6.95 (d, J=1.9 Hz, 1H), 6.86 (dd, J=8.7, 2.3 Hz, 2H), 6.80 (d,J=8.2 Hz, 1H), 6.49 (s, 1H), 3.48 (s, 1H), 2.08-1.86 (m, 2H), 1.74 (m,4H), 1.61 (m, 2H), 1.25-1.11 (m, 4H), 0.97-0.82 (m, 2H).

<Example 2-14>(S)-4-(6-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(24a)

Compound 21a (95 mg, 0.172 mmol) was dissolved in 1,4-dioxane (1.75 ml)and 4 M−HCl (0.87 ml) containing 1,4-dioxane was treated at roomtemperature. The reaction mixture was stirred at room temperature for 20minutes, the mixture was diluted with ether and then stirred until theproduct separated to a solid. The solid product was filtered off andwashed with ether followed by hexane. The crude product was thencrystallized to give Compound 24a (52 mg, 67%).

¹H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.17 (s, 1H), 7.99-7.92 (m, 3H),7.79 (d, J=26.2 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.57 (m, 3H), 7.33 (m,1H), 7.00 (dd, J=8.8, 2.4 Hz, 1H), 6.51 (s, 1H), 3.84 (s, 3H), 3.69 (s,1H), 3.43-3.20 (m, 1H), 2.96 (m, 2H), 2.81-2.53 (m, 2H), 1.99-1.45 (m,2H), 1.41-1.04 (m, 3H).

In the same manner as in Example 2-14, the compounds of Examples 2-15 to2-20 were obtained (Compound 24b (43 mg, 81%), 24c (110 mg, 90%), 24d(30 mg, 43%), 24e (110 mg, 62%), 24f (57 mg, 80%), 24g (118 mg, 77%)).

<Example 2-15>(S)-4-(6-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(24b)

¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=6.7 Hz, 2H), 7.76 (d, J=8.0 Hz,2H), 7.62 (d, J=8.4 Hz, 1H), 7.56 (m, 2H), 7.43 (m, 1H), 7.02 (s, 1H),6.97 (d, J=8.9 Hz, 1H), 6.78 (s, 1H), 4.15-3.80 (s, 1H), 3.60 (s, 3H),3.28-3.22 (m, 1H), 3.20-2.99 (m, 1H), 2.96 (m, 1H), 2.94-2.75 (m, 1H),2.62 (m, 2H), 1.87-1.60 (m, 1H), 1.39 (m, 1H), 1.24 (m, 2H).

<Example 2-16>(S)-4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(24c)

¹H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.87 (s,1H), 6.69 (m, 3H), 6.57 (d, J=8.7 Hz, 1H), 6.31 (s, 1H), 4.02-3.86 (m,4H), 3.69 (s, 1H), 3.54 (s, 3H), 3.04 (s, 1H), 3.03-2.96 (m, 2H),2.78-2.54 (m, 2H), 1.71 (m, 2H), 1.41 (m, 2H), 1.12-0.53 (m, 1H).

<Example 2-17>(S)-4-(2-(benzofuran-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(24d)

¹H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.23 (s,1H), 8.07 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.84 (d, J=8.5 Hz,1H), 7.63 (s, 1H), 7.40 (dd, J=8.8, 2.3 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H),7.08 (s, 1H), 4.25 (s, 3H), 4.04 (s, 1H), 3.65 (s, 1H), 3.38 (m, 2H),2.41 (m, 1H), 2.25 (m, 1H), 1.89 (m, 3H), 1.67 (m, 1H), 1.58-1.10 (m,1H).

<Example 2-18>(S)-4-(2-(3,4-dichlorophenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(24e)

¹H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 9.41 (m, 3H), 8.58-8.46 (m, 1H),8.26 (m, 1H), 7.90 (s, 1H), 7.74 (m, 2H), 7.50 (dd, J=8.4, 2.1 Hz, 1H),7.08 (dd, J=8.9, 2.1 Hz, 1H), 6.84-6.50 (m, 1H), 3.97 (m, 1H), 3.84 (s,3H), 3.55 (s, 1H), 3.45-3.28 (m, 1H), 3.15 (s, 1H), 3.09 (s, 1H), 2.80(m, 2H), 1.84 (m, 2H), 1.47 (m, 2H).

<Example 2-19>(S)-4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(24f)

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 7.88 (d, J=5.7 Hz, 1H), 7.82 (s,1H), 7.63 (d, J=8.8 Hz, 1H), 7.45 (m, 1H), 7.18 (s, 1H), 7.01 (dd,J=8.8, 2.3 Hz, 1H), 6.73 (s, 1H), 3.84 (s, 3H), 3.35 (s, 1H), 3.13 (m,2H), 2.87 (m, 2H), 2.18-1.86 (m, 2H), 1.63 (m, 3H), 1.26 (m, 1H).

<Example 2-20>(S)-4-(2-(benzo[d][1,3]dioxole-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine(24g)

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.17 (s,1H), 6.99 (dd, J=8.1, 1.5 Hz, 1H), 6.98-6.95 (m, 2H), 6.86 (d, J=8.1 Hz,1H), 6.62 (s, 1H), 6.02 (d, J=1.0 Hz, 1H), 6.01 (d, J=1.0 Hz, 1H), 4.00(s, 1H), 3.81 (s, 3H), 3.35 (s, 1H), 3.26 (m 1H), 3.05-2.86 (m, 2H),1.99 (m, 2H), 1.70 (m, 3H), 1.26 (m, 1H).

<Example 2-21>(S)-cyclopropyl(3-((4-(6-methoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(25a)

Compound 24a (52 mg, 0.12 mmol) was dissolved in THF (0.3 ml) and cooledto 0° C., then treated with TEA (24 μL). The mixture was addedcyclopropanecarbonyl chloride (10 mg) at 0° C., raised to roomtemperature, and stirred for 1 hour. The reaction mixture wasconcentrated in vacuum, diluted with methylene chloride and washed withwater and saturated aqueous sodium chloride solution. The organic layerwas dried over sodium sulfate, filtered, and the filtrate was distilledunder reduced pressure, and the residue was purified by columnchromatography (silica gel, DCM:MEOH 40:1) to obtain Compound 25a (31mg, 52%).

In the same manner as in Example 2-21, the compound of Examples 2-22 to2-27 was obtained (Compound 25b (27 mg, 97%), 25c (76 mg, 60%), 25d (20mg, 61%), 25e (16 mg, 39%), 25f (49 mg, 81%), 25g (60 mg, 66%)).

<Example 2-22>(S)-cyclopropyl(3-((4-(6-methoxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(25b)

¹H NMR (400 MHz, CD₃OD) δ 8.43 (d, J=8.5 Hz, 1H), 8.42-8.34 (m, 1H),8.18 (d, J=8.5 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.69 (dd, J=13.5, 6.1Hz, 2H), 7.61 (dd, J=12.6, 5.5 Hz, 2H), 7.32 (s, 1H), 7.05 (d, J=8.9 Hz,1H), 6.77 (s, 1H), 4.18-4.06 (br, 1H), 3.97 (m, 1H), 3.89 (s, 3H), 3.13(m, 1H), 2.86 (m, 2H), 1.91 (m, 1H), 1.48 (m, 4H), 1.22-1.03 (m, 1H),0.93-0.48 (m, 4H), 0.15 (m, 1H).

<Example 2-23>(S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(25c)

¹H NMR (400 MHz, CDCl₃) δ8.19 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.24 (s,1H), 7.07 (s, 1H), 6.98 (dd, J=8.4, 2.0 Hz, 1H), 6.93 (dd, J=8.8, 2.2Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.24 (s, 1H), 4.24 (d, J=5.0 Hz, 2H),4.21 (d, J=5.0 Hz, 2H), 4.15 (s, 1H), 3.87 (m, 1H), 3.44 (m, 1H),3.35-3.09 (m, 1H), 1.73 (m, 2H), 1.67-1.48 (m, 3H), 1.04-0.98 (m, 1H),0.92 (m, 1H), 0.86-0.78 (m, 2H), 0.73 (m, 1H), 0.34 (m, 1H).

<Example 2-24>(S)-(3-((4-(2-(benzofuran-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)(cyclopropyl)methanone(25d)

¹H NMR (400 MHz, CD₃OD) δ 8.41-8.22 (m, 1H), 7.84 (d, J=2.1 Hz, 2H),7.69-7.60 (m, 1H), 7.59-7.52 (m, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.29 (m,1H), 7.11-6.98 (m, 1H), 6.90 (s, 1H), 6.58 (s, 1H), 4.25 (m, 1H), 4.02(s, 1H), 3.84 (s, 3H), 3.29-3.08 (m, 1H), 2.95 (m, 1H), 1.98-1.84 (m,1H), 1.77 (s, 1H), 1.69-1.38 (m, 3H), 0.99-0.57 (m, 5H), 0.49-0.09 (m,1H).

<Example 2-25>(S)-cyclopropyl(3-((4-(2-(3,4-dichlorophenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(25e)

¹H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 7.86-7.70 (m, 2H), 7.45 (d,J=8.0 Hz, 1H), 7.35-7.28 (m, 1H), 7.20 (s, 1H), 7.01 (d, J=8.8 Hz, 1H),6.41 (s, 1H), 4.10 (s, 1H), 3.85 (s, 3H), 3.58 (s, 1H), 3.24 (m, 1H),1.76 (m, 3H), 1.05 (m, 5H), 0.92 (m, 5H).

<Example 2-26>(S)-cyclopropyl(3-((4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(25f)

¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.81 (d, J=32.4 Hz, 1H), 7.58(m, 2H), 7.16-7.02 (m, 2H), 6.88 (dd, J=8.8, 2.3 Hz, 1H), 6.29 (d,J=32.4 Hz, 1H), 3.96 (s, 1H), 3.72 (s, 3H), 3.61-3.35 (m, 2H), 1.72-1.52(m, 3H), 1.50-1.33 (m, 2H), 1.07-0.99 (m, 1H), 0.92-0.79 (m, 3H),0.77-0.59 (m, 3H).

<Example 2-27>(S)-(3-((4-(2-(benzo[d][1,3]dioxole-5-yl)-6-methoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)(cyclopropyl)methanone(25g)

¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.24 (s,1H), 7.02 (m, 2H), 6.94 (dd, J=8.6, 2.0 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H),6.35-6.14 (m, 1H), 5.98 (s, 2H), 4.16 (s, 1H), 3.81 (s, 3H), 2.01 (m,1H), 1.74 (s, 2H), 1.66 (m, 2H), 1.29-1.18 (m, 1H), 1.13 (m, 2H), 1.00(m, 3H), 0.85 (m, 2H), 0.74 (m, 1H).

<Example 2-28>(S)-cyclopropyl(3-((4-(6-hydroxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(26a)

After dissolving Compound 25a (27 mg, 0.053 mmol) in methylene chloride(05.3 ml), BBr₃ (25 μl) was added at −78° C. and stirred for about 1hour, and then stirred at room temperature for about 2 hours. Afterconfirming the completion of the reaction, methanol was added andquenched. The organic solvent was distilled under reduced pressure,extracted with methylene chloride, and washed with a saturatedNaHCO₃aqueous solution. The extracted organic layer was dried overmagnesium sulfate anhydrous, filtered, and the filtrate was distilledunder reduced pressure, and the residue was purified by columnchromatography (silica gel, methylene chloride:MeOH=20:1) to obtainCompound 26a (25 mg, 93%).

¹H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.3 (m, 2H), 7.92-7.95 (m,H),7.55-7.61 (m, 5H), 6.84 (dd, J=8.8, 2.0 Hz, 1H), 6.34-6.67 (m, 1H),3.87-4.39 (m, 3H), 2.80-3.05 (m, 1H), 1.98 (m, 1H), 1.34-1.51 (m, 4H),0.70-0.85 (m, 4H).

In the same manner as in Example 2-28, the compounds of Examples 2-29 to2-34 were obtained (Compound 26b, 26c (39 mg, 64%), 26d (3 mg, 18%), 26e(3 mg, 57%), 26f (5 mg, 65%), 26g).

<Example 2-29>(S)-cyclopropyl(3-(4-(6-hydroxy-2-(Quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone(26b)

¹H NMR (400 MHz, MeOD) δ 8.45 (m, 2H), 8.35-8.15 (m, 1H), 7.97 (s, 1H),7.79-7.57 (m, 3H), 7.22 (s, 1H), 6.97 (m, 1H), 6.77 (s, 1H), 4.07 (m,2H), 3.25-3.08 (s, 1H), 2.69 (m, 1H), 2.08-1.96 (m, 1H), 1.87-1.49 (m,4H), 1.29 (m, 3H), 0.89 (m, 3H), 0.65 (m, 1H).

<Example 2-30>(S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(26c)

¹H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.51-8.28 (m, 1H), 7.80-7.62 (m,1H), 7.53 (d, J=8.6 Hz, 1H), 7.01 (m, 1H), 6.90 (m, 2H), 6.79 (dd,J=8.6, 2.1 Hz, 1H), 4.26 (m, 4H), 4.19-4.07 (m, 1H), 3.86 (s, br, 1H),3.52 (m, 1H), 3.05 (m, 1H), 2.63 (m, 1H), 1.96 (m, 1H), 1.81 (m, 2H),1.64-1.35 (m, 2H), 1.21 (m, 1H), 0.83 (m, 3H), 0.58-0.01 (m, 2H).

<Example 2-31>(S)-(3-((4-(2-(benzofuran-5-yl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)(cyclopropyl)methanone(26d)

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.84 (m, 2H), 7.56 (dd, J=8.4,3.8 Hz, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.27-7.14 (m, 1H), 7.04 (dd,J=14.9, 8.4 Hz, 1H), 6.89 (d, J=8.2 Hz, 2H), 4.22 (s, br, 1H), 4.02 (s,1H), 3.17 (m, 1H), 2.84 (m, 2H), 2.10-1.96 (m, 2H), 1.81 (m, 2H), 1.56(m, 2H), 0.88 (m, 5H).

<Example 2-32>(S)-cyclopropyl(3-((4-(2-(3,4-dichlorophenyl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(26e)

¹H NMR (400 MHz, CD₃OD) δ 8.39 (d, J=57.2 Hz, 1H), 7.75 (s, 1H), 7.58(t, J=8.2 Hz, 2H), 7.37 (d, J=6.7 Hz, 1H), 7.05 (s, 1H), 6.91 (d, J=8.8Hz, 1H), 6.42 (d, J=5.3 Hz, 1H), 4.24 (d, J=12.4 Hz, 1H), 3.60 (s, 1H),3.27-3.13 (m, 1H), 3.09-2.61 (m, 2H), 2.01 (s, 1H), 1.92-1.50 (m, 5H),1.02-0.81 (m, 3H), 0.66-0.22 (m, 2H).

<Example 2-33>(S)-cyclopropyl(3-((4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone(26f)

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.91 (d, J=4.7 Hz, 1H), 7.77 (s,1H), 7.67-7.54 (m, 1H), 7.42 (m, 1H), 7.02 (s, 1H), 6.90 (d, J=8.7 Hz,1H), 6.37 (s, 1H), 4.14 (s, 1H), 3.59 (s, 1H), 2.15-1.95 (m, 2H), 1.59(m, 3H), 1.28 (m, 4H), 0.93-0.57 (m, 4H), 0.29 (m, 1H).

<Example 2-34>(S)-(3-(4-(2-([1,3]dioxolo[4,5-b]pyridin-5-yl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone(26g)

¹H NMR (400 MHz, DMSO) δ 9.34 (d, J=46.0 Hz, 2H), 8.48-8.23 (m, 1H),7.70 (d, J=32.8 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 6.96 (s, 1H), 6.76 (d,J=6.1 Hz, 2H), 4.19 (d, J=11.6 Hz, 1H), 3.88 (d, J=68.9 Hz, 1H), 2.87(d, J=96.9 Hz, 1H), 2.11-1.75 (m, 3H), 1.74-1.37 (m, 3H), 1.20 (d,J=23.5 Hz, 2H), 0.88-0.63 (m, 3H), 0.52 (d, J=37.8 Hz, 1H), 0.14 (d,J=90.2 Hz, 1H).

III. Synthesis of benzimidazol-5,6-diol Derivatives <Preparation Example3-1>4,5-dimethoxybezene-1,2-diamine (28)

Compound 27 (5 g, 21.9 mmol) was dissolved in methanol (147 ml), then10% Pd/C (639 mg) was added and stirred at room temperature for 6 hoursin the presence of hydrogen gas. After the reaction was completed, themixture was filtered through celite and the filtrate was distilled underreduced pressure. Compound 28 was obtained from the residue without anypurification. as a dark brown solid (99%); ¹H NMR (400 MHz, DMSO) δ 6.26(s, 2H), 4.11 (s, 4H), 3.58 (s, 6H).; LRMS (ESI) calcd for C₈H₁₂N₂O₂[M+H]+: 170, Found 170.

<Preparation Example3-2>5,6-dimethoxy-2-(naphthalenen-2-yl)-1H-benzo[d]imidazole etc.(Compounds 29a to 29e)

Compound 28 (2.97 mmol), R₁CHO (32.7 mmol) and Na₂S₂O₅ (148.5 mmol) weredissolved in DMF (29.7 ml) and stirred at 120° C., 150 W for 1 hour 30minutes in microwave. After confirming the completion of the reaction,the solvent was poured into iced water to precipitate. After theprecipitated reaction was filtered, the filtrate was distilled underreduced pressure, and the crude product was purified by flash columnchromatography on silica gel using a mobile phase of EA:HEX (3:1) toobtain Compounds 29a to 29e.

Compound 29a (5,6-dimethoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole)

as a yellow solid (50%); ¹H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 8.61(s, 1H), 8.25 (dd, J=8.6, 1.7 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 8.02-7.94(m, 2H), 7.61-7.53 (m, 2H), 7.14 (d, J=76.5 Hz, 2H), 3.83 (s, 6H).; LRMS(ESI) calcd for C₁₉H₁₆N₂O₂ [M+H]+: 305, Found 305.

Compound 29b (2-(3,4-dichlorophenyl)-5,6-dimethoxy-1H-benzo[d]imidazole)

as a yellow solid (56%); ¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 8.05(d, J=1.5 Hz, 1H), 7.82 (dd, J=8.4, 1.6 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H),7.02 (s, 2H), 3.80 (s, 6H).; LRMS (ESI) calcd for C₁₅H₁₂C₁₂N₂O₂ [M+H]+:324, Found 324.

Compound 29c(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6-dimethoxy-1H-benzo[d]imidazole)

as a yellow solid (65%); ¹H NMR (400 MHz, CDCl₃) δ 8.23-8.16 (m, 2H),7.15 (m, 1H), 7.09 (s, 2H), 3.84 (s, 6H).; LRMS (ESI) calcd forC₁₆H₁₂F₄N₂O₂[M+H]+: 341, Found 341.

Compound 29d(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dimethoxy-1H-benzo[d]imidazole)

as a white solid (45%); ¹H NMR (400 MHz, CDCl₃) 7.76 (d, J=8.9 Hz, 1H),7.30 (d, J=2.3 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 7.00-6.93 (m, 2H), 4.28(m, 2H), 4.27-4.23 (m, 2H), 3.87 (s, 6H).; LRMS (ESI) calcd forC₁₇H₁₆N₂O₄ [M+H]+: 313, Found 313.

Compound 29e (2-(benzofuran-5-yl)-5,6-dimethoxy-1H-benzo[d]imidazole)

as a yellow solid (67%); ¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H), 8.06(d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 6.91 (s, 2H),6.59 (s, 1H), 3.66 (s, 6H).; LRMS (ESI) calcd for C₁₇H₁₄N₂O₃ [M+H]+:295, Found 295.

<Preparation Example3-3>5,6-dimethoxy-1-(2-(methylthio)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazoleetc. (Compounds 30a to 30e)

Compound 29a to 29e (1.3 mmol), 4-chloro-2-(methylthio)pyrimidine (320mg, 1.3 mmol), palladium (II) acetate (Pd(oAc)₂) (88 mg, 0.13 mmol),X-Phos (62 mg, 0.13 mmol), and CS₂CO₃ were purged with nitrogen and thenmixed by addition of toluene (13 mL). After sonication under nitrogenfor 5 minutes, the mixture was heated to 130° C. under nitrogen andstirred at 130° C. for 3 hours without nitrogen. After cooling toambient temperature, the reaction mixture is filtered through acelitepad, the solvent is removed in vacuo and purified by flash columnchromatography on silica gel using a mobile phase of DCM:MEOH (40:1) toobtain Compound 30a to 30e.

Compound 30a(5,6-dimethoxy-1-(2-(methylthio)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazole)

as a yellow solid (27%); ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=5.4 Hz,1H), 8.22 (s, 1H), 7.88-7.83 (m, 3H), 7.59-7.49 (m, 4H), 7.41 (s, 1H),6.54 (d, J=5.4 Hz, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 2.56 (s, 3H).; LRMS(ESI) calcd for C₂₄H₂₀N₄O₂S [M+H]+: 429, Found 429.

Compound 30b(2-(3,4-dichlorophenyl)-5,6-dimethoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole)

as a yellow solid (35%); ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=5.4 Hz,1H), 7.73 (d, J=2.0 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.35 (s, 1H), 7.24(dd, J=8.5, 2.2 Hz, 2H), 6.57 (d, J=5.4 Hz, 1H), 3.92 (s, 3H), 3.89 (s,3H), 2.50 (s, 3H).; LRMS (ESI) calcd for C₂₀H₁₆C₁₂N₄O₂S [M+H]+: 448,Found 448.

Compound 30c2-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6-dimethoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole

as a yellow solid (37%); ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J=5.3 Hz,1H), 7.92 (d, J=5.0 Hz, 1H), 7.67-7.60 (m, 1H), 7.30 (d, J=6.3 Hz, 2H),7.21 (t, J=9.2 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 3.92 (d, J=9.7 Hz, 6H),2.46 (s, 3H).; LRMS (ESI) calcd for C₂₁H₁₆F₄N₄O₂S [M+H]+: 465, Found465.

Compound 30d(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dimethoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole)

as a yellow solid (42%); ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J=5.4 Hz,1H), 7.44 (s, 1H), 7.30 (s, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.96 (dd,J=8.4, 2.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.54 (d, J=5.4 Hz, 1H),4.29-4.25 (m, 2H), 4.23 (dd, J=3.7, 1.5 Hz, 2H), 3.93 (s, 3H), 3.90 (s,3H), 2.57 (s, 3H).; LRMS (ESI) calcd for C₂₂H₂₀N₄O₄S [M+H]+: 437, Found437.

Compound 30e(2-(benzofuran-5-yl)-5,6-dioxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole)

as a yellow solid (58%); ¹H NMR (400 MHz, DMSO) δ 9.07 (d, J=5.5 Hz,1H), 8.15 (d, J=2.4 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H), 8.01 (d, J=9.1 Hz,1H), 7.76 (d, J=8.6 Hz, 1H), 7.56 (dd, J=8.6, 1.7 Hz, 1H), 7.43 (m, 2H),7.16 (dd, J=9.1, 2.4 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 3.88 (s, 6H), 3.36(s, 3H).; LRMS (ESI) calcd for C₂₂H₁₈N₄O₅S [M+H]+: 451, Found 451.

<Preparation Example3-4>5,6-dimethoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazoleetc. (Compound 31a-31e)

Compound 30a to 30e (1 mmol) and potassium peroxomonosulfate (3.8 g)were dissolved in a mixed solvent of MeOH:H₂O=1:1 (5 ml) and stirred atroom temperature for 1 hour. When Compound 30a to 30e were disappearedfrom TLC, methanol was concentrated in vacuo. Water was added to themixture, diluted and stirred until the product separated to a solid. Thesolid product was filtered off and washed with water and then the crudeproduct was crystallized to obatain Compound 31a to 31e.

Compound 31a(5,6-dimethoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalene-2-yl)-1H-benzo[d]imidazole)

as a brown solid (68%); ¹H NMR (400 MHz, DMSO) δ 9.03 (d, J=5.6 Hz, 1H),8.29 (s, 1H), 8.04-7.99 (m, 3H), 7.80 (s, 1H), 7.64 (m, 3H), 7.47 (d,J=5.6 Hz, 1H), 7.42 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.35 (s, 3H).;LRMS (ESI) calcd for C₂₄H₂₀N₄O₄S [M+H]+: 461, Found 461.

Compound 31b(2-(3,4-dichlorophenyl)-5,6-dimethoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole)

as a white solid (60%); ¹H NMR (400 MHz, DMSO) δ 9.12 (d, J=5.5 Hz, 1H),7.94 (d, J=2.0 Hz, 1H), 7.73-7.69 (m, 2H), 7.61 (d, J=5.5 Hz, 1H),7.52-7.49 (m, 1H), 7.38 (s, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.39 (s,3H).; LRMS (ESI) calcd for C₂₀H₁₆C₁₂N₄O₄S [M+H]+: 480, Found 480.

Compound 31c(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6-dimethoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole)

as a white solid (70%); 1H NMR (400 MHz, DMSO) δ 9.11 (d, J=5.6 Hz, 1H),8.07 (dd, J=6.7, 1.9 Hz, 1H), 7.88 (m, 1H), 7.72 (d, J=12.8 Hz, 1H),7.63 (d, J=5.6 Hz, 1H), 7.59 (d, J=10.3 Hz, 1H), 7.41 (s, 1H), 3.85 (d,J=8.6 Hz, 6H), 3.16 (s, 3H).; LRMS (ESI) calcd for C₂₁H₁₆F₄N₄O₄S [M+H]+:497, Found 497.

Compound 31d(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dimethoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole)

as a white solid (65%); ¹H NMR (400 MHz, DMSO) δ 9.12 (d, J=5.5 Hz, 1H),7.93 (d, J=9.0 Hz, 1H), 7.51 (d, J=5.5 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H),7.19 (d, J=2.0 Hz, 1H), 7.10 (dd, J=9.0, 2.4 Hz, 1H), 7.02 (dd, J=8.4,2.0 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 4.33 (d, J=4.7 Hz, 2H), 4.30 (d,J=4.7 Hz, 2H), 3.86 (s, 6H), 3.41 (s, 3H).; LRMS (ESI) calcd forC₂₂H₂₀N₄O₆S [M+H]+: 469, Found 469.

Compound 31e(2-(benzofuran-5-yl)-5,6-dimethoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-benzo[d]imidazole)

as a white solid (70%); ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=5.4 Hz,1H), 7.83 (d, J=1.4 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.50 (m, 2H), 7.41(dd, J=8.6, 1.8 Hz, 1H), 7.32 (s, 1H), 6.77 (dd, J=2.2, 0.9 Hz, 1H),6.43 (d, J=5.4 Hz, 1H), 3.94 (d, J=7.7 Hz, 6H), 2.55 (s, 3H).; LRMS(ESI) calcd for C₂₂H₁₈N₄O₃S [M+H]+: 419, Found 419.

<Preparation Example 3-5> tert-butyl3-(4-(5,6-dimethoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-carboxylateetc. (Compound 32a-32e)

Compound 31a to 31e (1 mmol) and(S)-tert-butyl-3-aminopiperidine-1-carboxylate (2 mmol) were dissolvedin THF (10 ml) and stirred at 60° C. for 12 hours. After Compound 31a to31e disappeared in TLC, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude product was purified byflash column chromatography on silica gel using a mobile phase of HEX:EA(1:1) to obtain Compounds 32a to 32e.

Compound 32a (tert-butyl3-(4-(5,6-dimethoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate)

as a yellow solid (37%); ¹H NMR (400 MHz, MeOD) δ 8.28 (s, 1H), 8.13 (s,1H), 7.93-7.88 (m, 3H), 7.57 (m, 3H), 7.47 (s, 1H), 7.32 (s, 1H), 6.52(s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.69-3.58 (s, 1H), 3.20 (m, 1H),2.79 (m, 2H), 1.45 (s, 9H), 1.12 (m, 4H), 0.91 (m, 2H).; LRMS (ESI)calcd for C₃₃H₃₆N₆O₄ [M+H]+: 581, Found 581.

Compound 32b (tert-butyl3-(4-(2-(3,4-dichlorophenyl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate)

as a yellow solid (51%); ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.77(s, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.32 (dd, J=7.5, 2.9 Hz, 2H), 7.28-7.24(m, 1H), 6.31 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.84-3.59 (m, 2H),3.32 (s, 2H), 1.71 (m, 2H), 1.59-1.47 (m, 2H), 1.42 (m, 8H), 0.90 (m,1H).; LRMS (ESI) calcd for C₂₉H₃₂C₁₂N₆O₄S [M+H]+: 617, Found 617.

Compound 32c (tert-butyl3-(4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate)

as a yellow solid (53%); ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 7.93(d, J=4.9 Hz, 1H), 7.67 (s, 1H), 7.31 (s, 1H), 7.21 (m, 2H), 6.34 (d,J=3.4 Hz, 1H), 3.93 (d, J=15.5 Hz, 6H), 3.71-3.57 (s, 1H), 3.53-3.36 (m,1H), 3.30 (m, 2H), 1.69 (m, 2H), 1.46-1.42 (m, 3H), 1.40 (s, 9H), 1.22(m, 1H).; LRMS (ESI) calcd for C₃₀H₃₂F₄N₆O₄[M+H]+: 599, Found 599.

Compound 32d (tert-butyl3-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate)

as a yellow solid (57%); ¹H NMR (400 MHz, CDCl₃) δ8.23 (d, J=5.0 Hz,1H), 7.69 (d, J=8.5 Hz, 1H), 7.31 (s, 1H), 7.14 (s, 1H), 7.04 (d, J=7.9Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.23 (s, 1H),4.28 (d, J=4.9 Hz, 2H), 4.24 (d, J=4.9 Hz, 2H), 3.86 (s, 6H), 3.78 (s,1H), 3.45 (m, 2H), 3.37 (m, 1H), 1.66 (m, 2H), 1.53 (m, 2H), 1.43 (s,9H), 1.23 (m, 2H); LRMS (ESI) calcd for C₃₁H₃₆N₆O₆ [M+H]+: 589, Found589.

Compound 32e (tert-butyl3-(4-(2-(benzofuran-5-yl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate)

as a yellow solid (65%); ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=5.4 Hz,1H), 7.83 (d, J=1.4 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.50 (m, 2H), 7.41(dd, J=8.6, 1.8 Hz, 1H), 7.32 (s, 1H), 6.77 (dd, J=2.2, 0.9 Hz, 1H),6.43 (d, J=5.4 Hz, 1H), 3.94 (d, J=7.7 Hz, 6H), 2.55 (s, 3H).; LRMS(ESI) calcd for C₂₂H₁₈N₄O₅S [M+H]+: 451, Found 451.

<Preparation Example3-6>4-(5,6-dimethoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amineetc. (Compounds 33a-33e)

Compound 32a to 32e (0.033 mmol) were dissolved in 1,4-dioxane (0.33 ml)and 4 M−HCl (0.17 ml) containing 1,4-dioxane was treated at roomtemperature. The reaction mixture was stirred at room temperature for 20minutes, the mixture was diluted with ether and then stirred until theproduct separated to a solid. The solid product was filtered off andwashed with ether followed by hexane. The crude product was thencrystallized to obtain Compound 33a to 33e.

Compound 33a(4-(5,6-dimethoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine)

as a white solid (69%); ¹H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 8.10 (s,1H), 7.95-7.86 (m, 3H), 7.61-7.52 (m, 3H), 7.32 (s, 2H), 6.74 (s, 1H),3.94 (s, 3H), 3.92 (s, 3H), 3.73-3.46 (s, 1H), 3.19-2.92 (m, 2H), 2.68(m, 2H), 1.52 (m, 2H), 1.29 (m, 2H), 0.98-0.80 (m, 2H).; LRMS (ESI)calcd for C₂₈H₂₈N₆O₂ [M+H]+: 481, Found 481.

Compound 33b(4-(2-(3,4-dichlorophenyl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine)

as a yellow solid (78%); ¹H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 7.98 (s,1H), 7.81 (d, J=7.6 Hz, 1H), 7.62 (s, 1H), 7.41 (m, 2H), 6.90 (s, 1H),4.32 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.68-3.50 (m, 1H), 3.37 (m,1H), 3.00 (m, 2H), 2.03 (m, 2H), 1.79 (m, 2H), 1.64 (m, 1H); LRMS (ESI)calcd for C₂₄H₂₄C₁₂N₆O₂ [M+H]+: 500, Found 500.

Compound 33c(4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine)

as a white solid (80%); ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=21.5 Hz,1H), 7.93-7.76 (m, 2H), 7.39 (s, 1H), 7.31 (m, 1H), 7.17 (s, 1H), 6.56(s, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.70 (s, 1H), 3.46 (m, 1H), 3.33(s, 1H), 2.12-1.87 (m, 1H), 1.65 (m, 4H), 1.24 (m, 2H), 0.87 (m, 1H).;LRMS (ESI) calcd for C₂₅H₂₄F₄N₆O₂[M+H]+: 517, Found 517.

Compound 33d(4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine)

as a yellow solid (86%); ¹H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 7.30 (d,J=52.5 Hz, 2H), 7.10 (s, 1H), 7.03 (s, 1H), 6.94 (d, J=6.7 Hz, 1H), 6.63(d, J=131.7 Hz, 1H), 4.30 (d, J=8.5 Hz, 4H), 3.93 (d, J=10.6 Hz, 6H),3.67 (s, 1H), 3.43-3.26 (m, 4H), 3.03 (s, 2H), 2.19-1.96 (m, 2H),1.90-1.71 (m, 2H), 1.28 (s, 1H).; LRMS (ESI) calcd for C₂₆H₂₈N₆O₄[M+H]+: 489, Found 489.

Compound 33e(4-(2-(benzofuran-5-yl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)-N-(piperidine-3-yl)pyrimidin-2-amine)

as a yellow solid (89%); ¹H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 8.18 (s,1H), 8.08 (d, J=13.9 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.6 Hz,1H), 7.41 (s, 1H), 7.38 (s, 1H), 7.15 (s, 1H), 6.62 (s, 1H), 3.97 (s,1H), 3.90 (d, J=7.4 Hz, 6H), 3.23-2.99 (m, 2H), 2.74 (s, 3H), 2.02-1.70(m, 2H), 1.47 (d, J=87.5, 3H).; LRMS (ESI) calcd for C₂₆H₂₆N₆O₃ [M+H]+:471, Found 471.

<Preparation Example 3-7>(R)-cyclopropyl(3-(4-(5,6-dimethoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanoneetc. (34a to 34e)

Compound 33a to 33e (0.024 mmol) were dissolved in THF (0.24 ml) andcooled to 0° C., then treated with TEA (5 μL, 0.038 mmol). The mixturewas added cyclopropanecarbonyl chloride (6.5 mg, 0.024 mmol) at 0° C.,raised to room temperature, and stirred for 1 hour. The reaction mixturewas concentrated in vacuo, diluted with methylene chloride and washedwith water and saturated aqueous sodium chloride solution. The organiclayer was dried over sodium sulfate, filtered, and the filtrate wasdistilled under reduced pressure, and the residue was purified by columnchromatography (silica gel, DCM:MEOH 40:1) to obtain Compound 34a to34e.

Compound 34a((R)-cyclopropyl(3-(4-(5,6-dimethoxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone)

as a yellow solid (74%); ¹H NMR (400 MHz, MeOD) δ 8.33 (d, J=38.9 Hz,1H), 8.11 (d, J=7.0 Hz, 1H), 7.95-7.84 (m, 3H), 7.59-7.51 (m, 2H), 7.48(s, 1H), 7.33 (m, 2H), 6.66 (d, J=42.4 Hz, 1H), 4.13 (s, 1H), 3.94 (s,3H), 3.90 (s, 3H), 3.35 (s, 1H), 3.15 (m, 1H), 3.01-2.57 (m, 2H), 1.96(m, 1H), 1.61-1.40 (m, 2H), 1.28 (m, 2H), 0.95-0.76 (m, 3H), 0.60 (m,1H), 0.32 (m, 1H).; LRMS (ESI) calcd for C₃₂H₃₂N₆O₃ [M+H]+: 549, Found549.

Compound 34b((R)-cyclopropyl(3-(4-(2-(3,4-dichlorophenyl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone)

as a yellow solid (52%); ¹H NMR (400 MHz, MeOD) δ 8.51-8.39 (m, 1H),7.78 (s, 1H), 7.61 (dd, J=8.2, 5.4 Hz, 1H), 7.39 (dd, J=14.6, 8.2 Hz,1H), 7.32 (d, J=8.7 Hz, 2H), 6.60 (m, 1H), 4.28 (d, J=13.4 Hz, 1H),4.19-4.04 (s, 1H), 3.93 (d, J=14.9 Hz, 6H), 2.89 (s, 1H), 1.83 (m, 2H),1.62 (m, 3H), 1.41-1.25 (m, 2H), 0.93-0.75 (m, 3H), 0.67 (m, 1H), 0.34(m, 1H).; LRMS (ESI) calcd for C₂₈H₂₈C₁₂N₆O₃ [M+H]+: 568, Found 568.

Compound 34c((R)-cyclopropyl(3-(4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone)

as a yellow solid (38%); ¹H NMR (400 MHz, MeOD) δ 8.50-8.39 (m, 1H),7.92 (s, 1H), 7.78 (s, 1H), 7.43 (m, 1H), 7.30 (s, 2H), 6.60 (s, 1H),4.28 (m, 1H), 4.14 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 2.95-2.74 (m,1H), 2.06-1.92 (m, 1H), 1.75 (m, 2H), 1.68-1.46 (m, 2H), 1.28 (m, 2H),0.89 (m, 3H), 0.62 (m, 1H), 0.44-0.10 (m, 1H).; LRMS (ESI) calcd forC₂₉H₂₈F₄N₆O₃ [M+H]+: 585, Found 585.

Compound 34d((R)-cyclopropyl(3-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone)

as a yellow solid (38%); ¹H NMR (400 MHz, MeOD) δ 8.32 (s, 1H), 7.23 (s,2H), 7.00 (s, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.51(s, 1H), 4.29-4.24 (m, 4H), 3.90 (s, 3H), 3.85 (s, 3H), 3.54 (s, 1H),3.16-2.90 (m, 1H), 1.90-1.74 (m, 2H), 1.72-1.37 (m, 4H), 1.27 (m, 1H),0.93-0.75 (m, 3H), 0.63 (s, 1H), 0.43-0.07 (m, 1H).; LRMS (ESI) calcdfor C₃₀H₃₂N₆O₅ [M+H]+: 557, Found 557.

Compound 34e((R)-(3-(4-(2-(benzofuran-5-yl)-5,6-dimethoxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone)

as a yellow solid (38%); ¹H NMR (400 MHz, MeOD) δ 8.30 (s, 1H),7.94-7.77 (m, 2H), 7.57 (d, J=8.6 Hz, 1H), 7.42 (m, 2H), 7.29 (s, 1H),6.91 (s, 1H), 6.56 (s, 1H), 4.10-3.97 (s, 1H), 3.93 (s, 3H), 3.89 (s,3H), 3.68-3.56 (m, 1H), 2.93 (m, 1H), 1.88-1.73 (m, 2H), 1.63-1.51 (m,2H), 1.29 (m, 2H), 0.92-0.83 (m, 5H).; LRMS (ESI) calcd for C₃₀H₃₀N₆O₄[M+H]+: 539, Found 539.

<Example 3-1>(R)-cyclopropyl(3-(4-(5,6-dihydroxy-2-(naphthalene-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone(35a)

Compound 34a (0.053 mmol) was dissolved in methylene chloride (0.53 ml),BBr₃ (25 μl) was added at −78° C., stirred for about 1 hour, and againat room temperature for about 2 hours Was stirred. The mixture wasquenched with methanol (0.2 ml) at 0° C. and again stirred at rt for 1h. The mixture was diluted and extracted with methylene chloride (5 ml),washed three times with saturated aqueous NaHCO₃ solution (3 ml), twicewith 5 ml of water and twice with saturated sodium chloride solution (5ml). The organic phase was dried over sodium sulfate and concentrated invacuo to obtain the product as a white solid. The crude product waspurified by flash column chromatography on silica gel using a mobilephase of CH₂Cl₂:MeOH (40: 1-5:1) to obtain Compound 35a.

as a yellow solid (62%); ¹H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 8.12 (s,1H), 7.93 (m, 3H), 7.61-7.52 (m, 3H), 7.49 (s, 1H), 7.09 (s, 1H), 6.26(d, J=4.7 Hz, 1H), 3.83 (s, 1H), 3.41 (m, 2H), 3.17 (m, 2H), 2.94 (m,2H), 1.99 (s, 1H), 1.43 (m, 4H), 0.89-0.66 (m, 4H), 0.57 (m, 1H); LRMS(ESI) calcd for C₃₀H₂₈N₆O₃ [M+H]+: 521, Found 521.

In the same manner as in Example 3-1, the compounds of Examples 3-2 to3-5 were obtained (Compound 35b, 35c, 35d, 35e).

<Example 3-2>(R)-cyclopropyl(3-(4-(2-(3,4-dichlorophenyl)-5,6-dihydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone(35b)

as a yellow solid (58%); ¹H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 8.44 (d,J=44.8 Hz, 1H), 7.74 (s, 2H), 7.30 (d, J=39.1 Hz, 1H), 7.08 (s, 1H),6.57 (m, 1H), 4.26 (s, 1H), 3.91 (s, 1H), 2.99 (s, 1H), 2.84-2.53 (m,1H), 2.08-1.86 (m, 1H), 1.66 (m, 2H), 1.51 (m, 2H), 1.23 (m, 3H),0.88-0.65 (m, 3H), 0.57 (m, 1H), 0.25 (m, 1H).; LRMS (ESI) calcd forC₂₆H₂₄C₁₂N₆O₃ [M+H]+: 540, Found 540.

<Example 3-3>(R)-cyclopropyl(3-(4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-5,6-dihydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone(35c)

as a yellow solid (60%); ¹H NMR (400 MHz, MeOD) δ 8.36 (d, J=68.0 Hz,1H), 7.88 (d, J=4.4 Hz, 1H), 7.75 (s, 1H), 7.48-7.37 (m, 1H), 7.13 (d,J=6.5 Hz, 1H), 6.88 (d, J=147.6 Hz, 1H), 6.34 (s, 1H), 4.60 (s, 1H),4.31-3.82 (s, 2H), 3.13 (m, 1H), 2.76 (m, 1H), 2.06-1.70 (m, 3H), 1.60(m, 2H), 1.29 (m, 2H), 1.01-0.54 (m, 4H), 0.32 (m, 1H).; LRMS (ESI)calcd for C₂₇H₂₄F₄N₆O₃[M+H]+: 557, Found 557.

<Example 3-4>(R)-cyclopropyl(3-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dihydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone(35d)

as a yellow solid (42%); ¹H NMR (400 MHz, MeOD) δ 8.30 (s, 1H), 7.51 (s,1H), 7.12 (d, J=5.9 Hz, 1H), 7.02 (s, 1H), 6.95 (d, J=2.9 Hz, 1H),6.93-6.85 (m, 1H), 6.20 (d, J=5.0 Hz, 1H), 4.69 (s, 1H), 4.29 (m, 4H),3.93 (s, 1H), 3.57 (s, 1H), 3.22 (m, 1H), 2.87 (m, 1H), 1.96 (m, 3H),1.61 (m, 3H), 1.31 (m, 1H), 1.06-0.62 (m, 4H), 0.34 (m, 1H).; LRMS (ESI)calcd for C₂₈H₂₈N₆O₅ [M+H]+: 529, Found 529.

<Example 3-5>(R)-(3-(4-(2-(benzofuran-5-yl)-5,6-dihydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone(35e)

as a white solid (42%); ¹H NMR (400 MHz, MeOD) δ 8.36-8.07 (m, 1H), 7.84(d, J=1.9 Hz, 1H), 7.80 (s, 1H), 7.56 (m, 2H), 7.41 (d, J=7.7 Hz, 1H),7.13 (d, J=7.1 Hz, 1H), 6.90 (d, J=4.7 Hz, 1H), 6.11 (m, 1H), 4.22 (s,1H), 3.96 (s, 1H), 3.23 (s, 1H), 2.92 (m, 1H), 2.06-1.72 (m, 3H), 1.59(m, 3H), 1.15 (m, 2H), 0.86 (m, 3H), 0.67-0.20 (m, 2H).; LRMS (ESI)calcd for C₂₈H₂₆N₆O₄ [M+H]+: 511, Found 511.

Experimental Example 1. Measurement of JNK3 Enzymatic Activity

Changes in JNK3 enzymatic activity due to treatment with benzimidazolederivatives (Formula 1) according to the present invention wereconfirmed through IC₅₀.

First, a substrate was added to a prepared base reaction buffer solution(20 mM Hepes (pH 7.5), 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mlBSA, 0.1 mM Na₃VO₄, 2 mM DTT, 1% DMSO), a human JNK3 enzyme was addedinto the prepared substrate solution, and the resulting solution wasmixed. ATP (10 μM) and ATF2 (3 μM) were used as substrates, and amongthem, ATP was used as a common substrate. Next, the compound accordingto the present invention dissolved in 100% DMSO was added to an enzymereaction solution, and incubated at room temperature for 20 minutes.Subsequently, ³³P-ATP was added to the mixed reaction solution toinitiate the reaction, followed by incubation at room temperature for 2hours, and enzymatic activity was detected by a filter-binding method.Specifically, 25 al per resulting solution was slowly spotted on P81paper and placed in a scintillation vial, and then the paper was washedfour times with 0.75% phosphoric acid for 10 minutes each and washedonce with acetone for 5 minutes. 5 ml of a scintillation cocktail wasadded to the scintillation vial and signals were read using ascintillation counter.

As a result, IC₅₀ values of the benzimidazole derivatives according tothe present invention for JNK3 enzymatic activity are shown in Tables 1to 3 below, from which it was confirmed that the benzimidazolederivatives according to the present invention exhibited excellent JNK3inhibitory activity. In particular, it was confirmed that, thebenzimidazole derivatives of Formula 1 wherein 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, quinolinyl, or benzofuranyl wasintroduced into R₁, cyclopropyl methanone piperidinyl was introducedinto R₄, and a hydroxy group was introduced into both R₂ and R₃exhibited further enhanced JNK3 inhibitory activity.

TABLE 1 No R₁ R₂ R₃ R₄ JNK3 (IC₅₀, nM)  9a

H OH

+ 10a H OH

+ 13a H OH

++  9b

H OH

− 13b H OH

++  9c

H OH

+ 10c H OH

+ 13c H OH

++  9d

H OH

+ l0d H OH

+ 13d H OH

+++  9e

H OH

++ l0e H OH

+ 13e H OH

+++  9f

H OH

++ l0f H OH

+ 13f H OH

++ 13g

H OH

++ SP600125 ++ +: IC₅₀ > 100 nM ++: IC₅₀ = 30~100 nM +++: IC₅₀ < 30 nM

TABLE 2 No R₁ R₂ R₃ R₄ JNK3 (IC₅₀, nM) 22a

OH H

++ 23a OH H

+ 26a OH H

++ 22b

OH H

++ 23b OH H

+ 26b OH H

++ 22c

OH H

++ 23c OH H

+ 26c OH H

++ 22d

OH H

++ 23d OH H

+ 26d OH H

+++ 23e

OH H

++ 26e OH H

+++ 23f

OH H

+ 26f OH H

++ SP600125 ++ +: IC₅₀ > 100 nM ++: IC₅₀ = 30~100 nM +++: IC₅₀ < 30 nM

TABLE 3 No R₁ R₂ R₃ R₄ JNK3 (IC₅₀, nM) 35a

OH OH

+++ 35b

OH OH

+++ 35c

OH OH

+++ 35d

OH OH

+++ 35e

OH OH

+++ SP600125 ++ +: IC₅₀ > 100 nM ++: IC₅₀ = 30~100 nM +++: IC₅₀ < 30 nM

Experimental Example 2. Confirmation of Effect of Reducing Concentrationof Beta-Amyloid Oligomer in Brain Tissue Using Animal Model

JNK3 is known to phosphorylate and activate amyloid precursor protein(APP), which is the main cause of Alzheimer's disease, to thus allow theAPP to be located in a cell membrane, and promotes the conversion of APPto beta-amyloid, and it has been reported that, even in a case in which,after beta-amyloid is formed, the apoptosis of neurons is induced bytoxicity thereof, the activation of JNK3 acts as a main cause. Based onthese facts, in the present experimental example, the derivative of thepresent invention (compound 35d) was administered via intravenousinjection (IV) to Alzheimer's disease transgenic mice in a dose of 15mg/kg/day three times per 1 week for a total of 2 weeks, and thenchanges in the concentration of APP and beta-amyloid oligomer in thefrontal lobe cortex were confirmed through western blotting. Meanwhile,normal mice (WT(veh)) were used as a control, and non-treatedAlzheimer's disease transgenic mice (2×TG(veh)) were used as acomparative group.

As a result, as illustrated in FIG. 1, it was confirmed that, whentreated with the derivative according to the present invention, theexpression level of APP and the concentration of beta-amyloid oligomerwere significantly reduced compared to the comparative group. Takentogether, the results of Experimental Example 1 indicate that thederivatives according to the present invention having excellent JNK3inhibitory activity inhibit the formation of beta-amyloid, and thus areable to be effectively used for the treatment of neurodegenerative braindiseases such as Alzheimer' disease.

Experimental Example 3. Evaluation of Migration of Blood-Brain Barrier

The blood-brain barrier (BBB) functions as a primary barrier to preventthe invasion of foreign substances, but acts as an obstacle to treatmentin pathological circumstances. That is, therapeutics for the treatmentof brain diseases or maintaining the condition thereof are very unlikelyto permeate the blood-brain barrier, and thus are unable to beeffectively used, and accordingly, the selection of drugs for thetreatment of brain diseases is limited. Therefore, in the presentexperimental example, the possibility of an actual use of thederivatives according to the present invention (Compounds 26c and 35d)as drugs for the treatment of brain diseases was examined by confirmingwhether the derivatives were able to effectively permeate theblood-brain barrier. First, P-gp(MDR1)-overexpressing Caco-2-MDR1 cellswere plated on a BBB migration evaluation system constructed asillustrated in FIG. 2, and then the derivative according to the presentinvention and the like were added thereto, followed by incubation for acertain period of time. Subsequently, the concentration of derivativepresent in an apical chamber (A) and a basolateral chamber (B) wasmeasured and a permeability coefficient (P_(app)) was calculated byEquation 1 below. Meanwhile, caffeine and atenolol were used ascomparative materials.

P_(aap) =dQ/dt/CoA  [Equation 1]

(dQ/dt: the amount of material permeating into mebrain, A: area, and C₀:initial concentration of material)

As a result, as shown in Table 4 below, the derivative according to thepresent invention exhibited higher permeability than that of otherdrugs, as an effect due to hetero-substituents introduced into the R₁group, and thus may be anticipated to be highly effective in being usedas a therapeutic material for neurological brain diseases.

TABLE 4 Test A to B B to A Efflux Ratio Permeability Caffein 5.15 6.1611.20 High Atenolol 0.023 0.040 1.71 Limited Compound 26c 1.919 1.9851.03 High Compound 35d 1.728 1.956 1.13 High

The preferred embodiments of the present invention are provided to aidin understanding the present invention. However, the examples are merelyprovided to more easily understand the present invention, and thecontents of the present invention are not limited by the examples.

1. A benzimidazole derivative of Formula 1 or a pharmaceuticallyacceptable salt thereof:

wherein, in Formula 1, R₁ is selected from the group consisting ofbenzooxazolyl, benzodioxazolyl, 1,3-benzodioxolyl, 1,4-benzodioxinyl,dihydrobenzodioxinyl, benzothiazolyl, benzothiophenyl, quinolinyl,isoquinolinyl, indolyl, benzofuranyl, purinyl, and indolizinyl; R₂ andR₃ are each independently hydrogen or hydroxy; R₄ represents a C₃-C₁₀cycloalkyl or a C₄-C₁₀ heterocycloalkyl wherein the C₄-C₁₀heterocycloalkyl is selected from the group consisting oftetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, and piperidinyl; and R₄ may besubstituted or unsubstituted with a C₄-C₁₀ cycloalkylcarbonyl.
 2. Thebenzimidazole derivative of Formula 1 or a pharmaceutically acceptablesalt thereof, of claim 1, wherein, R₁ represents 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, quinolinyl, or benzofuranyl; R₂ and R₃are each independently hydrogen or hydroxy; R₄ is cyclohexyl,tetrahydropyranyl, or piperidinyl; and R₄ may be substituted orunsubstituted with a C₄-C₁₀ cycloalkylcarbonyl.
 3. The benzimidazolederivative of Formula 1 or a pharmaceutically acceptable salt thereof,of claim 1, R₁ represents 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, quinolinyl, or benzofuranyl; wherein, R₂and R₃ are each independently hydrogen or hydroxyl; and R₄ may becyclohexyl, tetrahydropyranyl, or cyclopropyl methanone piperidinyl. 4.The benzimidazole derivative of Formula 1 or a pharmaceuticallyacceptable salt thereof, of claim 1, wherein the benzimidazolederivative of Formula 1 is selected from the group consisting of thefollowing:2-(quinoline-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol;2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol;2-(benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-5-ol;1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazole-5-ol;2-(benzofuran-5-yl)-1-(2-(cyclohexylamine)pyrimidien-4-yl)-1H-benzo[d]imidazole-5-ol;(S)-cyclopropyl(3-((4-(5-hydroxy-2-(quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone;(S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone;(S)-(3-(4-(2-(benzofuran-5-yl)-5-hydroxy-1H-benz[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone;(S)-(3-(4-(2-(benzo[d][1,3]dioxol-5-yl)-5-hydroxy-1H-benz[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone;2-(quinoline-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol;2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-ylamino)pyriidine-4-yl)-1H-benzo[d]imidazole-6-ol;2-(benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol;3-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(quinoline-2-yl)-3H-benz[d]imidazole-5-ol;1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazole-6-ol;2-(benzofuran-5-yl)-1-(2-(cyclohexylamino)pyrimidin-4-yl)-1H-benzo[d]imidazole-6-ol;(S)-cyclopropyl(3-(4-(6-hydroxy-2-(quinoline-2-yl)-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone;(S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)methanone;(S)-(3-((4-(2-(benzofuran-5-yl)-6-hydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-yl)amino)piperidine-1-yl)(cyclopropyl)methanone;(R)-cyclopropyl(3-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-dihydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)methanone;or(R)-(3-(4-(2-(benzofuran-5-yl)-5,6-dihydroxy-1H-benzo[d]imidazole-1-yl)pyrimidin-2-ylamino)piperidine-1-yl)(cyclopropyl)methanone.5. A method of preventing or treating a degenerative neurologicaldisease, comprising administering to a subject a therapeuticallyeffective amount of a benzimidazole derivative or a pharmaceuticallyacceptable salt thereof, according to claim
 1. 6. The method of claim 5,wherein the neurodegenerative brain disease is selected from the groupconsisting of Alzheimer' disease, Parkinson' disease, Huntington'sdisease, multiple sclerosis, or stroke.
 7. The method of claim 5,wherein the pharmaceutical composition inhibits the activity of C-JunN-terminal kinase 3 (JNK 3).